Drug Discovery

In view of the numerous literature examples of the application of physicochemical meth-. 123 .... quantitative difference between the log L D 5 0 valu...
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5 Physicochemical Approaches to Drug Design

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WILLIAM P. PURCELL and JOHN M. CLAYTON Department of Molecular and Quantum Biology, College of Pharmacy, University of Tennessee Medical Units, Memphis, Tenn. 38103

One of the most potentially design

is the attempt

in molecular

structure

a quantitative

successful

approaches

to place correlations

with changes in biological

and predictive

level. While

have been made in this area by chemists of regression

analyses,

tions, and parameterization measurements.

molecular

It is concluded

therapeutic

agents without

pharmacological

pharmacoloillustrates

orbital

and

for the future in

exhaustive

the

calcula-

physicochemical

that quantitative

-activity studies hold some promise

on

efforts

and linear free-energy

lated models along with their modifications are reviewed.

activity

and

using various

The mathematical

drug

changes

qualitative

gists for over 100 years, more recent progress potential

to

between

synthetic

re-

applications structuredesigning work

and

screening.

" C o r over 100 years chemists a n d p h a r m a c o l o g i s t s h a v e b e e n i n t r i g u e d b y o b s e r v e d changes i n b i o l o g i c a l effects of c h e m i c a l congeners p a r a l l e l i n g s o m e w h a t m i n o r alterations i n m o l e c u l a r structure.

Following

m a n y successes a n d failures since the i n i t i a l w o r k , this interest continues to increase a m o n g m e d i c i n a l chemists as the l e v e l of s o p h i s t i c a t i o n of t h e m e t h o d s f o r s t u d y i n g a n d " i s o l a t i n g " these substituent effects i n d r u g d e s i g n i m p r o v e s . O f u l t i m a t e interest is the u t i l i z a t i o n of these t e c h n i q u e s to a c h i e v e a r a t i o n a l , c u s t o m d e s i g n of t h e r a p e u t i c agents a l o n g w i t h t h e e l u c i d a t i o n of a c t i v i t y m e c h a n i s m s at the s u b m o l e c u l a r l e v e l ( 1 ). It is necessary to p o i n t o u t i n i t i a l l y that i n a r e p o r t of this t y p e i t w o u l d b e v i r t u a l l y i m p o s s i b l e to i n c l u d e e v e r y w o r k that has b e e n significant to the d e v e l o p m e n t of the m e t h o d s p r e s e n t e d here.

W h i l e the

authors h a v e a t t e m p t e d to g i v e a representative s a m p l e of these c o n t r i b u t i o n s , t h e y h a v e n o t a t t e m p t e d a n exhaustive r e v i e w . I n v i e w of the n u m e r o u s literature examples of the a p p l i c a t i o n of p h y s i c o c h e m i c a l m e t h 123

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

124

DRUG DISCOVERY

ods to d r u g d e s i g n , the interested r e a d e r is r e f e r r e d to m o r e t h o r o u g h treatments of the m e t h o d o l o g y ( 1-3 ) a n d r e v i e w s of t h e r e c e n t l i t e r a t u r e (^8). I n the late 1860s C r u m - B r o w n a n d F r a s e r d e m o n s t r a t e d that g r a d u a l alterations i n m o l e c u l a r s t r u c t u r e of c e r t a i n d r u g s c o i n c i d e d w i t h changes i n t h e i r e l i c i t e d b i o l o g i c a l responses

(9).

T h e s e observations l e d to the

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p o s t u l a t e that the a c t i v i t y of a d r u g (φ) features ( C )

w a s a f u n c t i o n of its s t r u c t u r a l

(Equation 1). Φ = /(C)

(1)

Further, experimental w o r k on narcotic

agents i n 1893

led Richet

to

p o s t u l a t e that the degree of a c t i v i t y of the c o m p o u n d s w a s i n v e r s e l y r e l a t e d to t h e i r w a t e r s o l u b i l i t i e s (10).

Meyer and Overton expanded

this w o r k just at the t u r n of the t w e n t i e t h c e n t u r y to s h o w that the nar­ c o t i c activities of c e r t a i n congeners p a r a l l e l e d t h e i r o i l / w a t e r p a r t i t i o n i n g p r o p e r t i e s (11-15).

O f course, this p a r a m e t e r w a s d e s i g n e d to s i m u l a t e

the in vivo c o n d i t i o n of the drug's p a r t i t i o n i n g b e t w e e n a n aqueous b i o p h a s e a n d a l i p o p h i l i c site of a c t i o n .

I n 1907,

Fuhner

quantitatively

a p p r o x i m a t e d the b i o l o g i c a l responses of a h o m o l o g o u s series of narcotics (16,

17).

H e d e m o n s t r a t e d t h a t the decrease i n equiresponse

tions of these c o m p o u n d s f o l l o w e d a g e o m e t r i c ( 1 / 3 ) , ( 1 / 3 ) , etc.] 2

3

concentra­

progression

[1,

1/3,

as the n u m b e r of c a r b o n atoms i n c r e a s e d i n the

series. I n f u r t h e r investigations o f the r e l a t i o n s h i p b e t w e e n other p h y s i c o c h e m i c a l p r o p e r t i e s of m o l e c u l e s a n d t h e i r b i o l o g i c a l responses, in

1904

observed

a c t i o n (18).

a correlation between

surface

tension a n d

Traube narcotic

T h e s e d a t a l e d W a r b u r g to postulate a m e c h a n i s m of nar­

c o t i c a c t i o n f o r these agents i n 1921 (19).

S i m i l a r l y , i n 1917 M o o r e n o t e d

that the b o i l i n g p o i n t s of a series of i n s e c t i c i d e f u m i g a n t s p a r a l l e l e d t h e i r toxicities (20,

21).

A n i m p o r t a n t o b s e r v a t i o n i n s t r u c t u r e - a c t i v i t y studies was m a d e b y F e r g u s o n i n 1939 w h e n h e d e m o n s t r a t e d a n i n t e r r e l a t i o n s h i p a m o n g m u c h of the earlier w o r k (22).

E q u a t i o n 2 w a s p o s t u l a t e d to d e s c r i b e

b i o l o g i c a l responses of several c o n g e n e r i c series, w h e r e C

{

d

=

the

is the c o n c e n -

kA™i

(2)

t r a t i o n of c o n g e n e r i necessary to e l i c i t a d e f i n e d response, A i is a p h y s i c o c h e m i c a l or d e s c r i p t i v e p a r a m e t e r

f o r the c o m p o u n d (e.g., p a r t i t i o n

coefficient o r n u m b e r of c a r b o n atoms i n a side c h a i n ), a n d k a n d m are constants f o r the series.

S i n c e Ci is u s u a l l y less t h a n 1, the negative l o g a ­

r i t h m of E q u a t i o n 2 leads to E q u a t i o n 3, w h i c h is m o r e u s e f u l i n q u a n t i ­ tative s t r u c t u r e - a c t i v i t y studies a n d is a basis f o r s i m i l a r w o r k t o d a y (23,

24,

25).

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

5.

PURCELL AND CLAYTON

log

Physicochemical

=

q

-

log k -

125

Approaches

m l o g Ai

(3)

F u r t h e r a p p l i c a t i o n s of p h y s i c o c h e m i c a l parameters to b i o l o g i c a l a c t i v i ­ ties w e r e m a d e b y M c G o w a n (26, 27, 28).

H e has successfully c o r r e l a t e d

the b i o l o g i c a l activities of selected series of m o l e c u l e s w i t h t h e i r m o l e c u l a r v o l u m e s or p a r a c h o r s .

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F u r t h e r major c o n t r i b u t i o n s to, d e v e l o p m e n t of, a n d a p p l i c a t i o n s of q u a n t i t a t i v e s t r u c t u r e - a c t i v i t y correlations b e g a n i n 1956 w i t h t h e w o r k of B r u i c e a n d c o - w o r k e r s (29).

Their empirical, mathematical

method

w a s a p p l i e d to t h e c o r r e l a t i o n of t h y r o x i n e - l i k e activities of a series of congeners w i t h t h e s u m of constants a s s i g n e d to different substituents of the m o l e c u l e s .

U s i n g E q u a t i o n 4 t h e y o b t a i n e d excellent

correlations

log % t h y r o x i n e - l i k e a c t i v i t y = &Σ/ + c

(4)

b e t w e e n c a l c u l a t e d a n d o b s e r v e d activities. I n E q u a t i o n 4, 2/ = fx' + foR') w h e r e f , f >, a n d f ' x

x

(fx

+

a r e e n t i r e l y e m p i r i c a l a n d w e r e selected

0R

s i m i l a r to t h e m e t h o d of H a m m e t t f o r the e v a l u a t i o n of s i g m a constants. S u b s c r i p t s X , X ' , a n d OK structures of interest

represent substituent positions of t h e m o l e c u l a r

(29).

F r e e a n d W i l s o n gave a m o r e g e n e r a l d e s c r i p t i o n of this m a t h e m a t i c a l ( e m p i r i c a l ) m o d e l i n 1964 ( 30). b i o l o g i c a l response

A c c o r d i n g to t h e i r m e t h o d , t h e d e f i n e d

( B R ) of a congener i n a h o m o l o g o u s series is e q u a l

to t h e s u m of the substituent g r o u p c o n t r i b u t i o n s to t h e a c t i v i t y p l u s that of t h e p a r e n t structure ( μ ) , E q u a t i o n 5. F o r e x a m p l e , P u r c e l l has u s e d BR

= Σ (group c o n t r i b u t i o n s ) + μ

(5)

this m e t h o d i n s t u d y i n g the anticholinesterase potencies of a h o m o l o g o u s series of 3 - c a r b a m o y l p i p e r i d i n e s ( I )

(31).

If a m e t h y l g r o u p w e r e s u b -

R

R

2

3

I s t i t u t e d at p o s i t i o n R

t

a n d e t h y l groups w e r e s u b s t i t u t e d at positions R

a n d R , E q u a t i o n 5 w o u l d b e c o m e E q u a t i o n 6, w h e r e 3

BR

= [CH ] 3

R l

+ [C H ] 2

5

R 2

+ [C H ] 2

5

R 3

[CH ] 3

R l

+ μ

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2

is t h e (6)

126

DRUG DISCOVERY

activity

c o n t r i b u t i o n of

[C H ,]R 2

R

represents

2

a

methyl

group

substituted

at

position

Ri,

the a c t i v i t y c o n t r i b u t e d b y a n e t h y l g r o u p substi­

t u t e d at p o s i t i o n R , a n d [ C H ] R stands f o r the e t h y l g r o u p at R 2

2

3

5

I n v i e w of the a s s u m e d e q u i v a l e n c y of R

3

(31).

a n d R , the l i n e a r e q u a t i o n

2

3

c a n be s i m p l i f i e d b y r e d u c i n g the n u m b e r of u n k n o w n s , a n d E q u a t i o n 6 b e c o m e s E q u a t i o n 7.

A c c o r d i n g l y , a n e q u a t i o n is g e n e r a t e d

for

each

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compound. B R

=

[CH,]

R L

+

w i t h a m e a s u r e d b i o l o g i c a l response. equations)

2[C H ] 2

5

R 2

+

μ

(7)

I n a d d i t i o n , restrictions ( s y m m e t r y

are p l a c e d o n e a c h n o n e q u i v a l e n t substituent p o s i t i o n .

That

is, the s u m m a t i o n of the g r o u p c o n t r i b u t i o n s at e a c h n o n e q u i v a l e n t p o s i ­ t i o n m u s t e q u a l zero over the entire set of equations (30).

T h u s , f o r this

e x a m p l e , there w o u l d be t w o s y m m e t r y equations i n a d d i t i o n to the other equations.

T h e s i m u l t a n e o u s equations

b y the m e t h o d of least squares.

are t h e n s o l v e d i n d e p e n d e n t l y

S o l u t i o n of the equations y i e l d s the c a l ­

c u l a t e d a c t i v i t y c o n t r i b u t i o n of e a c h substituent g r o u p as w e l l as of the p a r e n t structure.

that

F o r c o m p a r i s o n w i t h the o b s e r v e d b i o l o g i c a l

activities, the c a l c u l a t e d t o t a l a c t i v i t y of each m o l e c u l e c a n b e o b t a i n e d b y s u m m a t i o n of these g r o u p c o n t r i b u t i o n s a n d μ (30).

The main pur­

pose of s u c h a treatment is to r a n k the b i o l o g i c a l activities of the sub­ stituent groups w h i l e n o t i n g possible s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s a n d to p r e d i c t the c o m p o u n d s of the series not tested, a n d p o s s i b l y n o t s y n ­ t h e s i z e d , w h i c h w o u l d h a v e the greatest p o t e n t i a l f o r f u r t h e r i n v e s t i g a ­ tion

(32). F o r a m e a n i n g f u l a p p l i c a t i o n of this m e t h o d , the b i o l o g i c a l d a t a

s h o u l d meet three basic prerequisites : ( 1 ) m o l e c u l e s i n the series s h o u l d be closely s i m i l a r to increase the p r o b a b i l i t y of t h e i r h a v i n g the

same

m e c h a n i s m of a c t i o n , ( 2 ) b i o l o g i c a l a c t i v i t y d a t a selected s h o u l d be a c c u ­ rate, q u a n t i t a t i v e , a n d m e a s u r e d u n d e r u n i f o r m c o n d i t i o n s f o r the series, and (3)

the g r o u p c o n t r i b u t i o n s m u s t b e i n t r i n s i c a l l y a d d i t i v e f o r the

c h o s e n a c t i v i t y parameters (32).

It is also d e s i r a b l e to h a v e a h i g h n u m b e r

of degrees of f r e e d o m since the greater the ratio of the n u m b e r of o b s e r v a ­ tions to the n u m b e r of u n k n o w n s , the m o r e r e l i a b l e are the results

(32).

R e c e n t l y , the p r o b l e m of i l l - c o n d i t i o n i n g has b e e n n o t e d w h e n this m e t h o d is a p p l i e d to c e r t a i n series of d a t a (33).

E x p l i c i t conditions for a p p l y i n g

the m e t h o d as w e l l as the statistical i n t e r p r e t a t i o n of the results

were

also d e f i n e d . T h e major l i m i t a t i o n of the m e t h o d lies i n the f a c t that the a c t i v i t y c o n t r i b u t i o n s of the substituents must be a d d i t i v e . T o date, most l i t e r a ­ t u r e examples of a p p l i c a t i o n s of this m e t h o d u n f o r t u n a t e l y h a v e

been

m a d e b y laboratories different f r o m the one w h i c h generated the d a t a .

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

5.

PURCELL AND CLAYTON

Physicochemical

127

Approaches

A m u c h m o r e d e s i r a b l e s i t u a t i o n exists w h e n d a t a g e n e r a t i o n a n d analysis are m a d e b y t h e same l a b o r a t o r y f o r o n l y t h e n are t h e n a t u r e , l i m i t a t i o n s , and quantitative reliability of the data fully realized a n d appreciated. A t a b o u t t h e t i m e of F r e e a n d W i l s o n ' s w o r k , K o p e c k y a n d c o - w o r k e r s introduced a similar mathematical T h e y tested f o u r equations

structure-activity model

(34,

35).

( E q u a t i o n s 8 - 1 1 ) f o r t h e expression o f t h e

q u a n t i t a t i v e difference b e t w e e n t h e l o g L D

values o f p- (34) a n d m-

5 0

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( 3 5 ) d i s u b s t i t u t e d benzenes a n d b e n z e n e . BA

= a

BA

= bjby

x

y

(9)

ΒA = c + c

dd

(10)

= c + c + dd

(11)

x

BA

(8)

+ a

x

y

-

x

y

x

y

y

I n E q u a t i o n s 8 - 1 1 a, b, c, a n d d represent the substituent c o n t r i b u t i o n to the t o t a l a c t i v i t y o f t h e c o m p o u n d s w h i l e t h e subscripts χ a n d y denote the substituent positions o n t h e p a r e n t m o l e c u l e .

Neither the additive

m o d e l ( n o t i c e a b l y s i m i l a r t o the F r e e - W i l s o n m o d e l )

(Equation 8), the

multiplicative model ( E q u a t i o n 9 ) , nor the combined model ( E q u a t i o n 10)

described the biological activity significantly.

T h e c o m b i n e d ex­

p r e s s i o n ( E q u a t i o n 1 1 ) , h o w e v e r , gave a statistically significant

corre­

l a t i o n b e t w e e n substituent a c t i v i t y a n d b i o l o g i c a l response f o r b o t h t h e m- (35) a n d p- (34) d i s u b s t i t u t e d series. A t t h e t i m e that t h e basic f o r m u l a t i o n a n d testing of t h e m a t h e m a t i c a l m o d e l s o f q u a n t i t a t i v e s t r u c t u r e - a c t i v i t y correlations w e r e b e i n g m a d e , another t y p e o f a p p r o a c h , t h e l i n e a r free-energy r e l a t e d m o d e l , w a s i n t r o ­ d u c e d (2).

U s i n g t h e basic H a m m e t t e q u a t i o n (22, 36) f o r the c h e m i c a l

reactions o f b e n z o i c a c i d d e r i v a t i v e s ( E q u a t i o n 12 ), several investigators a t t e m p t e d q u a n t i t a t i v e correlations b e t w e e n p h y s i c o c h e m i c a l p r o p e r t i e s log (/CXAH) =

ρσ

(12)

a n d b i o l o g i c a l response (1,37).

I n E q u a t i o n 12, k

l i b r i u m constants f o r reactions

of substituted a n d unsubstituted

x

a n d fc are t h e e q u i ­ H

com­

p o u n d s , r e s p e c t i v e l y , σ is a constant w h i c h d e p e n d s e n t i r e l y o n t h e n a t u r e a n d p o s i t i o n o f t h e substituent, a n d ρ is a constant w h i c h d e p e n d s o n t h e t y p e a n d c o n d i t i o n s o f r e a c t i o n as w e l l as t h e n a t u r e o f t h e c o m p o u n d (22).

R e w r i t t e n as E q u a t i o n 13, t h e H a m m e t t e q u a t i o n c l e a r l y illustrates log k

x

= ρσ + l o g

fc

H

(13)

the l i n e a r r e l a t i o n s h i p b e t w e e n t h e substituent constant σ a n d t h e l o g a ­ r i t h m of the r e a c t i v i t y of t h e c o m p o u n d ( f c ) (1,38). x

Since the logarithm

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

128

DRUG

DISCOVERY

of a n e q u i l i b r i u m constant is p r o p o r t i o n a l to the change i n G i b b s free energy

( E q u a t i o n 14)

energy r e l a t e d " (38).

E q u a t i o n 13 a n d others l i k e it are

(39),

"free-

I n E q u a t i o n 14, R is the i d e a l gas constant, AF° AF°

=

-

is (14)

RT In k

the G i b b s free energy change, Τ is absolute temperature, a n d k is the Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 27, 2015 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch005

e q u i l i b r i u m constant for the r e a c t i o n . A p p l i c a t i o n s of this H a m m e t t l i n e a r free-energy r e l a t e d e q u a t i o n to several b i o l o g i c a l systems b y v a r i o u s i n ­ vestigators, h o w e v e r , y i e l d e d o n l y l i m i t e d success f r o m about 1952 1966 (37, 40-A7).

to

S u c h a p p l i c a t i o n s l e d H a n s e n to p r o p o s e a " b i o l o g i c a l "

H a m m e t t e q u a t i o n w i t h a restrictive set of c o n d i t i o n s f o r a p p l i c a t i o n (48).

E v e n w i t h these restrictions, h o w e v e r , i t has met w i t h o n l y l i m i t e d

success. T h e use of the H a m m e t t e q u a t i o n was e x t e n d e d b y Z a h r a d n i k a n d c o - w o r k e r s to relate other p h y s i c o c h e m i c a l parameters

of

homologous

series of c o m p o u n d s to t h e i r b i o l o g i c a l activities ( E q u a t i o n 15)

(49).

I n E q u a t i o n 15, τ is the m o l a r c o n c e n t r a t i o n of the i t h congener of a n {

log (τ,·/τ *) β

= αφ

(15)

a l i p h a t i c h o m o l o g o u s series necessary to e l i c i t a d e f i n e d b i o l o g i c a l re­ sponse, τ

is the m o l a r c o n c e n t r a t i o n of the e t h y l d e r i v a t i v e of the series

et

r e q u i r e d to p r o d u c e a s i m i l a r response, α is a constant w h i c h d e p e n d s u p o n the nature of the series of c o m p o u n d s a n d the b i o l o g i c a l system, a n d β is a p h y s i c o c h e m i c a l p a r a m e t e r stituent.

w h i c h d e p e n d s u p o n the

sub­

V a r i o u s types of β h a v e b e e n u s e d , i n c l u d i n g the H a m m e t t a n d

T a f t constants, o n several h o m o l o g o u s series i n v a r i o u s b i o l o g i c a l systems A g a i n the use of a single parameter, h o w e v e r , to define a b i o ­

(49-52).

l o g i c a l response has g i v e n correlations of l i m i t e d significance. R e c o g n i z i n g the p h y s i c o c h e m i c a l n a t u r e of b i o l o g i c a l reactions

and

r e a l i z i n g the i m p o r t a n c e of p a r t i t i o n i n g i n a drug's r e a c h i n g its site of a c t i o n (53,

54),

H a n s c h a n d c o - w o r k e r s e x p a n d e d the l i n e a r free-energy

r e l a t e d expression i n 1964 to i n c l u d e a d d i t i o n a l p h y s i c o c h e m i c a l p a r a m ­ eters (55, 56, 57).

F o l l o w i n g the a p p r o a c h of T a f t ( 5 8 )

i n the l i n e a r

c o m b i n a t i o n of t w o constants, t h e y d e r i v e d a n e w expression

(Equation

16) f o r the c o r r e l a t i o n of b i o l o g i c a l a c t i v i t y w i t h m o l e c u l a r structure i n l o g (1/C)

= *rx +

w h a t is c a l l e d the "ρ-σ-π e q u a t i o n " ( 5 5 ) .

ρσ + k

(16)

2

C represents the m o l a r c o n c e n ­

t r a t i o n of a congener necessary to elicit a d e f i n e d b i o l o g i c a l response, ΤΓ is the substituent p a r t i t i o n i n g p a r a m e t e r d e f i n e d as the difference b e t w e e n the l o g a r i t h m s of the o c t a n o l / w a t e r

p a r t i t i o n coefficients

of the

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

sub-

5.

PURCELL AND CLAYTON

Physicochemical

129

Approaches

stituted a n d u n s u b s t i t u t e d p a r e n t c o m p o u n d i n the series the H a m m e t t substituent constant, a n d k

p, a n d k

l9

2

erated b y regression analysis of the series.

( 5 9 ) , σ is

are constants

gen­

A l t h o u g h a l l t h e terms are

free-energy r e l a t e d a n d a p p r o x i m a t e true t h e r m o d y n a m i c constants, t h e e q u a t i o n is t e r m e d " e x t r a t h e r m o d y n a m i c " since these parameters

are

u s e d i n systems other t h a n those s i m i l a r to the systems i n w h i c h they

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w e r e d e t e r m i n e d (55,

60).

A f t e r m e e t i n g w i t h m u c h success i n c o r r e l a t i n g the s t r u c t u r e - r e ­ sponse d a t a i n a w i d e v a r i e t y o f systems (7, 61), this basic e q u a t i o n w a s m o d i f i e d b y a d d i n g or s u b s t i t u t i n g a v a r i e t y of parameters i n attempts to d e s c r i b e better the activities of n u m e r o u s c o m p o u n d s .

O n e of t h e

foremost m o d i f i c a t i o n s of this basic e q u a t i o n has b e e n the postulate that the b i o l o g i c a l response to a d r u g is p a r a b o l i c a l l y a n d n o t l i n e a r l y r e l a t e d to its p a r t i t i o n i n g properties r e s u l t i n g i n the i n c l u s i o n of a π t e r m (56, 2

57, 62).

A l t h o u g h i t m a y seem that the parameters i n E q u a t i o n 16 are

s o m e w h a t a r b i t r a r y a n d h i g h l y e m p i r i c a l , it c a n be s h o w n that these variables c a n b e d e r i v e d f r o m first p r i n c i p l e s . Justification f o r t h e m m a y b e a p p a r e n t w h e n o n e considers the r a n d o m w a l k process b y w h i c h a d r u g reaches its site of a c t i o n . Since the m o l e c u l e must cross a series of l i p o i d a l m e m b r a n e s o r barriers, the e l i c i t e d response d e p e n d s m o r e o n its c o n c e n t r a t i o n at the receptor site t h a n o n the q u a n t i t y of d r u g a d m i n ­ istered ( 5 6 ) . T h e r e f o r e , the rate of b i o l o g i c a l response m a y b e g i v e n b y : d(response)/ift =

ACkx

(17)

w h e r e A is the p r o b a b i l i t y of a molecule's r e a c h i n g its receptor site, C is the c o n c e n t r a t i o n of d r u g a d m i n i s t e r e d , a n d k

x

is the e q u i l i b r i u m or rate

constant i n v o l v e d at the active site. AC w o u l d t h e n represent the effec­ tive i n t r a c e l l u l a r c o n c e n t r a t i o n of d r u g .

T o a p p l y this e q u a t i o n p r a c ­

t i c a l l y , i t is necessary to d e t e r m i n e e x p e r i m e n t a l l y the values of A a n d kx (56).

It w a s f o r this a p p r o x i m a t e e v a l u a t i o n of A that t h e -π t e r m w a s

derived while k

x

w a s a p p r o x i m a t e d b y the H a m m e t t σ p a r a m e t e r

(22).

If one assumes a n o p t i m u m π v a l u e of ττ f o r a m a x i m u m e l i c i t e d re­ 0

sponse a n d assumes the b i o l o g i c a l response f o l l o w s a n o r m a l G a u s s i a n d i s t r i b u t i o n w i t h respect to π w h i l e other factors are h e l d constant, E q u a ­ t i o n 18 i n w h i c h a a n d b are constants is o b t a i n e d A = /(*) = a e x p [ -

(z -

(56).

r. y/b]

(18)

o

E x p a n s i o n of E q u a t i o n 18 y i e l d s E q u a t i o n 19. A s s u m i n g that ττ is c o n 0

A = a exp [(— π + 2ττ 2

0

— π )/6] 0

2

(19)

stant f o r a p a r t i c u l a r series of congeners i n the g i v e n b i o l o g i c a l system, one obtains E q u a t i o n 20, w h e r e c a n d d are constants r e p l a c i n g the terms

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

130

DRUG DISCOVERY

= a exp [ ( -

A i n 7τ . 0

x

+

2

cx +

(20)

d)/b]

S u b s t i t u t i n g E q u a t i o n 20 i n t o E q u a t i o n 17 y i e l d s E q u a t i o n 21,

w h e r e the rate of b i o l o g i c a l response is r e p l a c e d b y a constant, k', a exp [ ( -

k' =

x

+

2

cx +

since (21)

d ) / b ] Ck

x

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one is interested i n the response l e v e l d u r i n g a specific t i m e i n t e r v a l rather t h a n its rate.

T a k i n g the l o g a r i t h m of E q u a t i o n 21 a n d r e a r r a n g i n g the

terms gives E q u a t i o n 22, i n w h i c h the constants f r o m E q u a t i o n 21 h a v e log (1/C) =

-

&x + 2

/dx +

k

log k

+

2

b e e n c o m b i n e d to y i e l d s i m p l i f i e d constants, k, k

a n d k>.

u

of E q u a t i o n 12 f o r l o g k

(22)

x

and incorporating —log k ,

x

h o m o l o g o u s series, i n t o constant e q u a t i o n ( E q u a t i o n 23)

Substitution

constant

u

for a

results i n the w i d e l y u s e d H a n s c h

k

2

(56).

l o g (1/C) =

-

/cx + /cix +

ρσ +

2

(23)

k

2

A p p l i c a t i o n of this e q u a t i o n to series of b i o l o g i c a l d a t a i n v o l v e s the s u m m a t i o n of the p h y s i c o c h e m i c a l parameters f o r a l l of the

substituents

a l o n g w i t h the g e n e r a t i o n of a n e q u a t i o n of the f o r m of E q u a t i o n for e a c h o b s e r v a t i o n . log

24

F o r example, H a n s c h a n d D e u t s c h have a p p l i e d

(l/C)

=

&Σχ

2

+

ΑαΣχ +

ρΣσ

+

(24)

k

2

this m e t h o d to s t u d y the s t r u c t u r e - a c t i v i t y correlations of 2 , 6 - d i a l k o x y phenylpenicillins (II) OR

i n the presence of s e r u m

(63).

2

CO—NH—CH—CH

OR

I

I

OC

Ν

C—(CH ) 3

2

1 CH—COOH

2

II W h e n a m e t h y l g r o u p is s u b s t i t u t e d at R i w i t h h y d r o g e n s at e q u i v a l e n t positions R , the r e s u l t i n g ρ-σ-π e q u a t i o n is E q u a t i o n 25. 2

l o g (1/C)

=

-

Â;(* CH + 2

3

P(*CH + 3

2x

2

H

) + Αα(ποΗ + 3

Simultaneous

2*H)

+

2 σ ) + kz Η

(25)

s o l u t i o n of t h e e q u a t i o n s g e n e r a t e d f o r e a c h of the e i g h t m e m b e r s of this series gives E q u a t i o n 26.

S i n c e the c o r r e l a t i o n coefficient, r, is a m e a s u r e

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

5.

Physicochemical

PURCELL AND CLAYTON

l o g (1/C) = O . O l x of t h e goodness

2

-

0.316z +

o f fit b e t w e e n

131

Approaches

1.76σ +

1.853

r = 0.930

(26)

the calculated a n d observed data, the

e q u a t i o n appears to d e s c r i b e a d e q u a t e l y t h e b i o l o g i c a l response p a r a m ­ eters

(63). T h e r e a l v a l u e of this e x t r a t h e r m o d y n a m i c a p p r o a c h to d r u g d e s i g n

lies i n its flexibility to m o d i f i c a t i o n b y i n c o r p o r a t i n g or d e l e t i n g a v a r i e t y

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of p h y s i c o c h e m i c a l parameters.

F o r e x a m p l e , i t m a y b e u s e d to e l u c i d a t e

the m e c h a n i s m o f d r u g a c t i o n at t h e s u b m o l e c u l a r l e v e l b y d e t e r m i n a t i o n of t h e r e l a t i v e i m p o r t a n c e of e a c h p a r a m e t e r i n d e s c r i b i n g t h e b i o l o g i c a l response.

I n the above example, H a n s c h a n d D e u t s c h used modifications

of E q u a t i o n 24 i n attempts to isolate substituent effects ( E q u a t i o n s 27 a n d 28) (63).

A n a l y s i s of the d a t a u s i n g t h e π p a r a m e t e r alone ( E q u a t i o n

=

log ( I / O log ( I / O 27) y i e l d e d r =

=

*ix +

(27)

k

2

*ιπ + kv + 2

(28)

k,

0.823 w h i l e i n c l u s i o n of σ w i t h π ( E q u a t i o n 28)

gave

r = 0.929. C o m p a r i s o n of t h e c o r r e l a t i o n coefficients of E q u a t i o n s 26 a n d 28 i n d i c a t e s that t h e ?r t e r m does n o t m a k e a significant c o n t r i b u t i o n t o 2

the b i o l o g i c a l response (63).

E x t e n s i o n of this i d e a to a n o t h e r b i o l o g i c a l

system has s h o w n that the e l e c t r o n i c p a r a m e t e r σ m a d e a significant c o n ­ t r i b u t i o n to the a c t i v i t y i n that p a r t i c u l a r system (64).

T h i s illustrates

the p r o b l e m i n v o l v e d i n t h e p r o p e r selection of p a r a m e t e r

combinations

to d e s c r i b e a d e q u a t e l y b i o l o g i c a l response i n different systems. A n o t h e r p o t e n t i a l use of this l i n e a r free-energy c u s t o m t a i l o r i n g a d r u g is p a r a m e t e r

related method i n

optimization. Once a particular

series of d a t a has b e e n a n a l y z e d , o n e m a y e v a l u a t e π f o r t h e series a n d 0

m a k e this t h e starting p o i n t i n s u g g e s t i n g m o l e c u l e s f o r f u r t h e r synthesis a n d testing.

U s e of this a p p r o a c h also m i g h t i n d i c a t e that a different

series of c o m p o u n d s s h o u l d b e c o n s i d e r e d i f o p t i m u m parameters

have

a l r e a d y b e e n a c h i e v e d i n t h e c o m p o u n d s tested ( 1 ). A s w a s true i n the m a t h e m a t i c a l a p p r o a c h , one of t h e foremost l i m i t a ­ tions of this m e t h o d is its d e p e n d e n c e o n accurate, q u a n t i t a t i v e b i o l o g i c a l data.

I n a d d i t i o n , t h e q u a n t i t a t i v e n a t u r e of t h e l i n e a r free-energy r e ­

l a t e d m o d e l is l i m i t e d b y t h e a c c u r a c y of t h e e x p e r i m e n t a l p h y s i c o c h e m ­ i c a l parameters as w e l l as t h e i r a p p l i c a b i l i t y i n systems s o m e w h a t distant to those i n w h i c h t h e y w e r e d e t e r m i n e d . A l t h o u g h t h e p l o t of H a m m e t t σ values gives a d i s t i n c t b r e a k i n l i n e a r r e l a t i o n s h i p p a r a l l e l i n g a s u d d e n c h a n g e i n m e c h a n i s m of a c t i o n

(38,

65),

such a change

i n biological

m e c h a n i s m of a c t i o n m a y n o t b e r e a d i l y d e t e c t e d i n t h e H a n s c h analysis. A l s o , at t h e present t i m e , there is n o a p p a r e n t means to d e t e r m i n e w h e t h e r a n a d m i n i s t e r e d d r u g o r some m e t a b o l i t e of this d r u g is r e s p o n s i b l e f o r a n

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

132

DRUG DISCOVERY

e l i c i t e d response f r o m c o n g e n e r to c o n g e n e r i n this a p p r o a c h .

Despite

these l i m i t a t i o n s , h o w e v e r , this m e t h o d does offer a basis o r s t a r t i n g p o i n t f o r i n c r e a s i n g t h e l e v e l o f s o p h i s t i c a t i o n a n d a c c u r a c y to d e s c r i b e m o r e a d e q u a t e l y t h e c o m p l e x i t y o f events s u r r o u n d i n g d r u g

response.

I n a d d i t i o n to these attempts at q u a n t i t a t i v e s t r u c t u r e - a c t i v i t y m o d e l b u i l d i n g , a t h e o r e t i c a l a p p r o a c h , q u a n t u m c h e m i s t r y , has b e e n u s e d to s t u d y c h e m i c a l c o m p o u n d s of b i o l o g i c a l interest ( I , 3 , 66).

I n this c o n -

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n e c t i o n , o n e s h o u l d m e n t i o n t h e major c o n t r i b u t i o n s of t h e P u l l m a n s i n a p p l y i n g q u a n t u m c h e m i s t r y to b i o l o g y since 1950 (67-71).

Their work

o n t h e p o s s i b l e m e c h a n i s m of c h e m i c a l carcinogenesis i n terms of q u a n tum

m e c h a n i c a l p r o p e r t i e s as w e l l as c a l c u l a t i o n s o n t h e n u c l e i c a c i d

constituents has p r o v i d e d m u c h of t h e f o u n d a t i o n f o r t h e i n c r e a s i n g i n terest i n q u a n t u m b i o l o g y .

A t a somewhat

more fundamental level,

L o w d i n has also b e e n a p i o n e e r i n t h e a p p l i c a t i o n of q u a n t u m m e c h a n i c s to p r o b l e m s of b i o l o g i c a l interest

H i s t h e o r e t i c a l c a l c u l a t i o n s of

(72).

the p r o p e r t i e s o f t h e n u c l e i c a c i d base p a i r s has l e d to a p r o p o s e d m e c h a nism of D N A replication. In

1965 N e e l y p u b l i s h e d a n e x a m p l e of t h e u t i l i t y of m o l e c u l a r

o r b i t a l t h e o r y i n c o r r e l a t i o n studies (73).

T h i s s t u d y i l l u s t r a t e d t h e use

of q u a n t u m c h e m i c a l c a l c u l a t i o n s as a n a i d i n c o r r e l a t i n g m o l e c u l a r structure of selected o r g a n o p h o s p h a t e s terase i n h i b i t o r y potencies.

a n d carbamates w i t h their cholines-

K i e r has b e e n another p i o n e e r i n u t i l i z i n g

quantum

mechanics

(74-80).

F r o m several types of c a l c u l a t i o n s h e has p r e d i c t e d t h e p r e -

to p o s t u l a t e

ferred conformations

the nature

of isolated molecules

of biological

receptors

of b i o l o g i c a l interest a n d

r e l a t e d t h e i r l o w e s t e n e r g y c o n f o r m a t i o n s to t h e n a t u r e of t h e i r receptors (80). M o r e r e c e n t l y n u m e r o u s investigators h a v e m a d e w i d e use of these b a s i c m e t h o d s i n t h e p h y s i c o c h e m i c a l a p p r o a c h to d r u g d e s i g n .

Using

the m a t h e m a t i c a l m o d e l of F r e e a n d W i l s o n ( 3 0 ) , B e a s l e y a n d P u r c e l l h a v e g i v e n t h e first e x a m p l e of the successful p r e d i c t i o n of t h e a c t i v i t y of a c o m p o u n d b e f o r e its synthesis (81).

I n 1965 P u r c e l l r e p o r t e d t h e p r e -

d i c t e d b u t y r y l c h o l i n e s t e r a s e i n h i b i t o r y p o t e n c y of l - d e c y l - 3 - ( N - e t h y l - N methylcarbamoyl)piperidine hydrobromide, C H , R = C H ) (31). 2

5

3

3

(I, R i =

Ci H i, 0

2

R2

=

T h r e e years later this c o m p o u n d w a s s y n t h e s i z e d

a n d e v a l u a t e d b i o c h e m i c a l l y . T h e o b s e r v e d a n d p r e d i c t e d response values a g r e e d w i t h i n e x p e r i m e n t a l error (81).

B a n a n d F u j i t a h a v e also a p p l i e d

this m e t h o d to t h e n o r e p i n e p h r i n e u p t a k e i n h i b i t i o n o f selected p a t h o m i m e t i c amines (82).

sym-

A g a i n , excellent correlations w e r e o b t a i n e d

b e t w e e n c a l c u l a t e d a n d e x p e r i m e n t a l response

values.

M o r e r e c e n t efforts h a v e b e e n c o n c e r n e d w i t h attempts to correlate structure w i t h a c t i v i t y , u t i l i z i n g m i n o r m o d i f i c a t i o n s of the l i n e a r freee n e r g y r e l a t e d m o d e l s (4, 5, 6, 8, 83).

A l t h o u g h the basic transport a n d

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

5.

PURCELL AND CLAYTON

Physicochemical

133

Approaches

e l e c t r o n i c parameters a r e u s u a l l y r e t a i n e d , several parameters other t h a n π a n d σ have been studied. H a n s c h a n d co-workers obtained

excellent

c o r r e l a t i o n s i n a w i d e v a r i e t y o f studies u s i n g l o g Ρ i n s t e a d of t h e s u b ­ stituent

7Γ p a r a m e t e r

where

of t h e c o m p o u n d (84, 85).

Ρ is d e f i n e d as t h e p a r t i t i o n

coefficient

T h e in vitro p a r t i t i o n i n g system o f interest

f o r t h e in vivo s i m u l a t i o n c o n t i n u e s to b e that of o c t a n o l a n d w a t e r

(86).

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A l t h o u g h other p a r t i t i o n i n g systems w e r e s t u d i e d [ s u c h as o l e y l a l c o h o l / water

(87)1,

v e r y l i t t l e i m p r o v e m e n t , i f a n y , has b e e n s h o w n i n t h e

correlations u s i n g other p a r t i t i o n i n g systems (86).

Others have obtained

excellent s t r u c t u r e - a c t i v i t y correlations b y a p p r o x i m a t i n g t h e t r a n s p o r t phenomenon w i t h the chromatographic parameter R

(88S3).

m

M o r e extensive p a r a m e t e r v a r i a t i o n s h a v e b e e n r e p o r t e d i n t h e a p ­ proximation of electronic

substituent

parameters.

I n a d d i t i o n to t h e

w i d e l y used σ value, numerous workers have applied the Taft σ * param­ eter (58, 60) to a l i p h a t i c systems w i t h v a r y i n g degrees o f success (2, 4, 8, 94, 95). (μ)

M c F a r l a n d has suggested t h e use of g r o u p d i p o l e m o m e n t s

a n d e l e c t r o n i c p o l a r i z a b i l i t y parameters ( a ) i n a d d i t i o n t o H a m m e t t

σ values t o e x p l a i n better t h e e l e c t r o n i c interactions b e t w e e n d r u g s a n d receptors (96, 97).

H e o b t a i n e d excellent results i n c o r r e l a t i n g i n h i b i t o r y

rate constants of E. colt b y c h l o r a m p h e n i c o l analogs ( E q u a t i o n 2 9 ) l o g (1/C) = β χ ζ

2

+

kK + 2

kG + Z

& μ + hoc +

(96). (29)

h

4

M o r e r e c e n t l y h e has g i v e n a n extensive d e r i v a t i o n o f t h e t h e o r e t i c a l basis f o r i n c l u d i n g b o t h t h e μ a n d a parameters 2

(97).

C l a y t o n a n d P u r c e l l h a v e i l l u s t r a t e d t h e p r e d i c t i v e u t i l i t y o f this m e t h o d w h e n a p p l i e d t o selected b u t y r y l c h o l i n e s t e r a s e i n h i b i t o r s

(94).

T h e y o b t a i n e d q u a n t i t a t i v e correlations u s i n g σ * values, a m i d e g r o u p d i p o l e m o m e n t s , a n d μ i n a d d i t i o n to h y d r o p h o b i c parameters.

In addi­

t i o n , H a n s c h a n d c o - w o r k e r s h a v e u s e d T a f t steric parameters (E )

(60)

a n d ρ Κ values to o b t a i n excellent correlations i n v a r i o u s systems

(84).

s

α

E has r e c e n t l y b e e n s h o w n t o b e q u a n t i t a t i v e l y r e l a t e d to v a n d e r W a a l ' s s

r a d i i f o r s y m m e t r i c a l t o p - l i k e substituents

(98)

w h i l e pK

a

values h a v e

b e e n u s e d as a m e a s u r e of e l e c t r o n d e n s i t y d i s t r i b u t i o n s (99).

Fukuto

a n d c o - w o r k e r s c o m b i n e d Taft's E a n d σ * parameters i n a p h y s i c o c h e m ­ 8

i c a l a p p r o a c h to t h e m o d e of a c t i o n of o r g a n o p h o s p h o r u s insecticides (95 ). M o d i f i e d H a m m e t t substituent constants (100) w e r e u s e d b y G a r r e t t et al. t o d e s c r i b e t h e b a c t e r o s t a t i c a c t i v i t i e s of a series of s u l f a n i l a m i d e s (101).

H a n s c h also u s e d t h e h o m o l y t i c s u b s t i t u e n t constants (E ) R

Y a m a m o t o a n d O t s u (102)

of

i n a n a l y z i n g t h e a c t i v i t y o f selected c h l o r ­

a m p h e n i c o l d e r i v a t i v e s (103).

T h e r e s u l t i n g correlations l e d to t h e h y ­

pothesis o f a f r e e - r a d i c a l m e c h a n i s m of c h l o r a m p h e n i c o l a c t i o n .

Sub­

stituent measures o f π e l e c t r o n c h a r g e d e n s i t y d i s t r i b u t i o n s (σι a n d σ ) π

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

134

DRUG DISCOVERY

w e r e u s e d b y S a s a k i a n d S u z u k i to i l l u s t r a t e t h e d e p e n d e n c e of

(104)

p a r t i t i o n coefficients a n d b i o l o g i c a l a c t i v i t y o n m o l e c u l a r e l e c t r o n i c c o n ­ ditions (105). I n a d d i t i o n to these, t h e use of several other t h e r m o d y n a m i c s u b ­ stituent constants has b e e n i n v e s t i g a t e d (1, 4, 106). t r e n g a u s e d m o l a r a t t r a c t i o n constants (107,108),

F o r example, Os-

a n d T u r n e r a n d Batter-

s h e l l h a v e c o r r e l a t e d c h e m i c a l r e a c t i v i t i e s , v a p o r pressures, a n d p a r t i t i o n

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coefficients o f a series o f i s o p h t h a l o n i t r i l e s w i t h t h e i r f u n g i c i d a l p r o p ­ erties

(109).

Jones a n d c o - w o r k e r s u s e d regression analyses to s t u d y t h e eifects of field

constants a n d resonance parameters

(110)

o f some c a r b a m a t e d e ­

r i v a t i v e s o n t h e i r p e n e t r a t i o n a n d d e t o x i c a t i o n w i t h some success

(111).

S i m i l a r studies h a v e also b e e n m a d e b y F u k u t o a n d c o - w o r k e r s u s i n g selected

oximes a n d t h e i r anticholinesterase

activities

(112).

Kakeya

et al. u s e d c h e m i c a l shifts a n d v a l e n c e force constants i n a d d i t i o n t o other t h e r m o d y n a m i c parameters i n t h e s t r u c t u r e - a c t i v i t y s t u d y of a series o f sulfonamide carbonic anhydrase inhibitors

(113).

T h e c o m b i n a t i o n of q u a n t u m m e c h a n i c a l c a l c u l a t i o n s a n d t h e l i n e a r free-energy r e l a t e d m o d e l has b e e n u s e d r e c e n t l y b y several investigators i n d r u g a c t i v i t y studies—i.e., a v a r i e t y of i n d i c e s o b t a i n e d f r o m t h e q u a n ­ t u m c h e m i c a l c a l c u l a t i o n s has b e e n u t i l i z e d i n these correlations (4, 8, F o r e x a m p l e , N e e l y a n d c o - w o r k e r s o b t a i n e d excellent correlations

114).

b e t w e e n t h e energy of t h e highest o c c u p i e d m o l e c u l a r o r b i t a l , a r e l a t i v e m e a s u r e of t h e a b i l i t y of a m o l e c u l e to d o n a t e a n e l e c t r o n to a n a c c e p t o r m o l e c u l e , o f a series of i m i d a z o l i n e s a n d t h e i r a n a l g e t i c potencies

(115).

I n a n analysis o f t h e l i n e a r free-energy r e l a t i o n s h i p s i n d r u g - r e c e p t o r i n t e r a c t i o n s , C a m m a r a t a has s h o w n a t h e o r e t i c a l i n t e r p r e t a t i o n of sub­ stituent constants i n a b i o l o g i c a l context

(116, 117).

H e has s e p a r a t e d

the free e n e r g y c h a n g e o c c u r r i n g i n a r e a c t i o n i n t o its electronic, d e s o l v a t i o n , a n d steric c o m p o n e n t s , d e f i n e d e a c h i n terms o f its c o n t r i b u t i o n s , a n d a p p r o x i m a t e d these c o n t r i b u t i o n s w i t h q u a n t u m m e c h a n i c a l i n d i c e s (118, 119).

U s i n g a t o m i c o r b i t a l coefficients a n d t o t a l e l e c t r o n i c

charge

o n c e r t a i n p o r t i o n s o f t h e m o l e c u l e , C a m m a r a t a o b t a i n e d excellent

cor­

relations b e t w e e n q u a n t u m m e c h a n i c a l i n d i c e s a n d s u l f a n i l a m i d e a c t i v i t y (120) . H e also suggested t h e use o f π net charge, ττ-electrophilic a n d n u c l e o p h i l i c s u p e r d e l o c a l i z a b i l i t i e s , a n d energy l e v e l differences to inter­ pret drug-receptor selected (121)

interactions.

cholinesterase

W h e n this a p p r o a c h w a s a p p l i e d to

inhibitors, he obtained very good

correlations

.

H e r m a n n et al. o b t a i n e d g o o d correlations b e t w e e n t h e r e l a t i v e sub­ strate efficiencies of some acetophenones t o w a r d r a b b i t k i d n e y reductase a n d selected

q u a n t u m m e c h a n i c a l parameters

(122).

T h e substituent

indices were derived f r o m electron density calculations a n d energy dif-

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

5.

PURCELL AND CLAYTON

Physicochemical

135

Approaches

ferences b e t w e e n g r o u n d a n d i n c i p i e n t t r a n s i t i o n states (122).

I n the

s t u d y of t h e D N A i n t e r c a l a t i o n b y c h l o r o q u i n e d e r i v a t i v e s , Bass et (123)

ah

c a l c u l a t e d s i g m a - e l e c t r o n c h a r g e d i s t r i b u t i o n s a n d u s e d these i n

a d d i t i o n to other substituent parameters t o investigate a m e c h a n i s m p r o p o s e d b y O ' B r i e n a n d H a h n (124)

for antimalarial activity. T h e deriva-

t i o n of a n d r a t i o n a l e b e h i n d t h e i n c l u s i o n o f this t e r m i n t o t h e H a n s c h e q u a t i o n w e r e also g i v e n

(123).

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It m a y seem t h a t t h e v a r i o u s structure—activity m o d e l s a n d p a r a m eters are n o t t r u l y so i n d e p e n d e n t as t h e y a r e p r e s e n t e d here. this s u s p i c i o n is justified.

Certainly

Recently, Singer a n d P u r c e l l evaluated the

i n t e r r e l a t i o n s h i p s a m o n g t h e q u a n t i t a t i v e structure—activity m o d e l s a n d i l l u s t r a t e d t h e i r s i m i l a r i t i e s (125).

A l s o , t h e parameters

m o d e l s c a n n o t b e t o t a l l y i n d e p e n d e n t of o n e another. tempts

t o find those parameters

u s e d i n these O n e m e r e l y at-

w h i c h alone o r i n c o m b i n a t i o n

best

d e s c r i b e t h e b i o l o g i c a l a c t i v i t y . I n v i e w of this, L e o et al. h a v e r e p o r t e d a c o m p a r i s o n of the parameters c u r r e n t l y u s e d i n studies of this t y p e

(86).

A p a r t f r o m t h e i r use i n l i n e a r free-energy r e l a t e d equations, q u a n t u m m e c h a n i c a l c a l c u l a t i o n s h a v e b e e n u s e d i n other w a y s i n d r u g d e s i g n studies.

N a g y a n d N a d o r f o u n d that t h e c e n t r a l e x c i t i n g effect of a m -

p h e t a m i n e s increases w i t h a decrease of the n e g a t i v e charge, as determ i n e d b y q u a n t u m m e c h a n i c a l m e t h o d s , o n t h e s e c o n d c a r b o n of t h e benzene

ring

(126).

C o r c o d a n o c a l c u l a t e d the r i n g c a r b o n

reactivity

i n d i c e s of some p h e n y l a c e t i c a c i d d e r i v a t i v e s a n d s h o w e d that this p a r a m eter correlates w e l l w i t h t h e i r a u x i n i c activities (127).

U s i n g the H i i c k e l

m o l e c u l a r o r b i t a l m e t h o d , M a i n s t e r a n d M e m o r y p r o p o s e d that

super-

d e l o c a l i z a b i l i t y m a y b e u s e d i n c h a r a c t e r i z i n g c h e m i c a l c a r c i n o g e n s ( 128 ). I n other studies, P u r c e l l a n d S u n d a r a m u s e d the s u m of t h e e n e r g y of t h e h i g h e s t o c c u p i e d m o l e c u l a r o r b i t a l ( H O M O ) a n d that of the l o w e s t e m p t y m o l e c u l a r o r b i t a l ( L E M O ) as a measure of m o l e c u l a r electronegat i v i t y w h e n a p p l i e d to q u i n o l i n e m e t h a n o l a n t i m a l a r i a l s (129).

Sharpless

a n d G r e e n b l a t t f o u n d e l e c t r o n d e n s i t y , L E M O , a n d p K v a l u e s to correa

late w e l l w i t h t h e a c r i d i n e toxicities to v a r i o u s m i c r o o r g a n i s m s

(130).

T h e s e correlations h a v e l e d t o t h e i r p o s t u l a t i o n of a m e c h a n i s m of a c t i o n . I n a final e x a m p l e , A n d r e w s u s e d q u a n t u m c h e m i c a l m e t h o d s to c a l c u l a t e the d i p o l e m o m e n t s of a series of a n t i c o n v u l s a n t d r u g s a n d r e l a t e d c o m pounds

(131).

T h e s e c a l c u l a t i o n s suggest a m e c h a n i s m of a c t i o n f o r

these d r u g s different f r o m that w h i c h h a d b e e n p r o p o s e d p r e v i o u s l y ( 132 ). O n e a d d i t i o n a l area of i n c r e a s i n g interest

i n the physicochemical

a p p r o a c h to d r u g d e s i g n is t h e use of i n s t r u m e n t a l m e t h o d s , p a r t i c u l a r l y n u c l e a r m a g n e t i c resonance ( N M R ) . w o r k e r s (133, 134),

Pioneered b y Jardetzky a n d co-

t h e use of N M R i n studies of drug—receptor inter-

actions at the m o l e c u l a r l e v e l is s h o w i n g great p r o m i s e .

This

technique

is u s e d p r i m a r i l y t o f o l l o w t h e c h a n g e effected i n t h e r e l a x a t i o n rates o f

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

136

DRUG DISCOVERY

t h e p r o t o n s of a s m a l l m o l e c u l e u p o n b i n d i n g to a m a c r o m o l e c u l e

by

o b s e r v i n g d i f f e r e n t i a l p e a k b r o a d e n i n g of its N M R s p e c t r u m . I n a d d i t i o n , changes i n the c h e m i c a l shift of the N M R s p e c t r u m of the s m a l l m o l e c u l e h a v e b e e n u s e d to investigate s u b s t r a t e - r e c e p t o r

interactions.

T h u s far,

N M R has b e e n a p p l i e d su c c e ssf u lly to the s t u d y of e n z y m e - s u b s t r a t e i n teractions

(135,

136),

enzyme-coenzyme

z y m e - i n h i b i t o r interactions

(136,

138).

interactions

and

(137),

en-

A l t h o u g h the l i t e r a t u r e is be-

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g i n n i n g to s h o w n u m e r o u s in vitro examples of the u t i l i t y of N M R i n this area, one r e c e n t a p p l i c a t i o n has u s e d the intact c e l l u l a r system ( 139 ).

In

this s t u d y , F i s c h e r a n d Jost d i r e c t l y o b s e r v e d the i n t e r a c t i o n of e p i n e p h r i n e w i t h its r e c e p t o r site i n the m o u s e l i v e r c e l l a n d w e r e able to postulate the n a t u r e of the i n t e r a c t i o n ( 139 ). A s is the case w i t h the other p h y s i c o c h e m i c a l m e t h o d s , h o w e v e r , the p o t e n t i a l of the a p p l i c a t i o n of N M R to d r u g d e s i g n is great, b u t m u c h d e v e l o p m e n t lies a h e a d f o r its r e a l i z a t i o n . A d v a n c e s h a v e b e e n a n d are b e i n g m a d e i n the p h y s i c o c h e m i c a l a p proaches to d r u g d e s i g n . A l t h o u g h progress has b e e n s l o w i n d e v e l o p i n g q u a n t i t a t i v e s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s b e c a u s e of the

complexity

of the b i o l o g i c a l systems u n d e r l y i n g a n o b s e r v a b l e response f r o m a d r u g a n d there is n o p r o m i s e that these t e c h n i q u e s offer a p a n a c e a

in drug

d e s i g n , there is great p o t e n t i a l i n " d i s s e c t i n g the r o l e of the i m p o r t a n t m o l e c u l a r forces at w o r k w h i c h y i e l d different b i o l o g i c a l responses i n the series of c o n g e n e r s "

(140)

a n d i n using physicochemical methods

for

selecting p r o m i s i n g m o l e c u l e s f o r synthesis a n d e v a l u a t i o n . A s i n v i r t u a l l y a l l areas of scientific a d v a n c e m e n t , the v a r i o u s areas of e n d e a v o r are at different levels of s o p h i s t i c a t i o n .

F o r example,

one

k n o w s m o r e a b o u t the m o l e c u l a r structure of a n i s o l a t e d m o l e c u l e f r o m i n s t r u m e n t a l analyses t h a n a b o u t the specific i n t e r a c t i o n of this m o l e c u l e w i t h a c o m p l i c a t e d b i o l o g i c a l system.

I l l u s t r a t i n g this c o n d i t i o n i n a n -

other w a y , one c o u l d say that the l e v e l of s o p h i s t i c a t i o n of h a n d l i n g s i m u l t a n e o u s equations is greater t h a n the u n d e r s t a n d i n g of a p a r a m e t e r f r o m p h a r m a c o l o g i c a l testing. It is i m p o r t a n t , h o w e v e r , to r e c o g n i z e that c e r t a i n areas w i l l l a g b e h i n d others as one attempts m o r e rigorous interpretations i n interactions b e t w e e n m o l e c u l e s a n d b i o l o g i c a l systems.

In

the a u t h o r s ' o p i n i o n , this does not m e a n that w o r k s h o u l d stop i n one area i n o r d e r f o r the l e v e l of s o p h i s t i c a t i o n to " c a t c h u p " i n another area. R a t h e r , the entire a c t i v i t y s h o u l d m o v e a l o n g w i t h o u t the

investigators'

b e c o m i n g p r e o c c u p i e d w i t h the i m b a l a n c e of the levels of d e v e l o p m e n t of the areas of a c t i v i t y . F o r e x a m p l e , i t is most f o r t u n a t e that the d e r i v a t i o n of the S c h r o d i n g e r e q u a t i o n (141)

d i d not " w a i t " f o r the d e v e l o p m e n t of

h i g h s p e e d d i g i t a l c o m p u t e r s , w h i c h c o u l d g i v e p r a c t i c a l a p p l i c a t i o n to its solution.

This analogy holds for d r u g design.

T h a t is, one s h o u l d c o n -

t i n u e efforts to p u t structure—activity r e l a t i o n s h i p s o n a q u a n t i t a t i v e l e v e l e v e n t h o u g h there are l i m i t a t i o n s to the significance of c e r t a i n b i o l o g i c a l

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

5.

PURCELL AND CLAYTON

Physicochemical

137

Approaches

a c t i v i t y d a t a . A s l o n g as t h e investigators are a w a r e of these l i m i t a t i o n s , it is a p p r o p r i a t e to c o n t i n u e to refine the m o d e l s . F e w p e o p l e w o u l d h a v e p r e d i c t e d a successful " m o o n w a l k , " a n d f e w w o u l d t r y to p r e d i c t t h e t i m e at w h i c h n e w d r u g m o l e c u l e s

can be

d e s i g n e d s p e c i f i c a l l y w i t h o u t exhaustive synthetic w o r k a n d p h a r m a c o ­ l o g i c a l s creen in g.

T h e p o t e n t i a l of p r e d i c t i n g a c c u r a t e l y t h e b i o l o g i c a l

a c t i v i t y of a m o l e c u l e b e f o r e its synthesis

does a p p e a r

to exist;

only

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c o n t i n u e d w o r k i n this area a n d t i m e w i l l d e t e r m i n e w h e t h e r or n o t this p o t e n t i a l is r e a l .

Acknowledgment T h e authors g r a t e f u l l y a c k n o w l e d g e s u p p o r t b y the U . S. A r m y M e d i ­ cal Research

a n d Development C o m m a n d (DA-49-193-MD-2779),

the

N a t i o n a l S c i e n c e F o u n d a t i o n ( G B - 7 3 8 3 ) , t h e C o t t o n P r o d u c e r s Institute, a g r a n t f r o m E l i L i l l y C o . , a n d a N a t i o n a l Institutes of H e a l t h F e l l o w s h i p (5FOl-GM43,699-02)

f r o m t h e N a t i o n a l Institute

of G e n e r a l M e d i c a l

Sciences d u r i n g t h e p e r i o d this m a n u s c r i p t w a s w r i t t e n .

Literature Cited (1) Purcell, W. P., Singer, J. Α., Sundaram, K., Parks, G. L., in "Medicinal Chemistry, " 3rd ed., A. Burger, Ed., Chap. 10, Wiley, New York, 1970. (2) Hansch,C.,in "Drug Design," Vol. I, E. J.Ariëns,Ed., Academic, New York, in press. (3) Kier, L. B., Ed., "Molecular Orbital Studies in Chemical Pharmacology," Springer-Verlag, New York, 1970. (4) Clayton, J. M., Millner, Ο. E., Jr., Purcell, W. P., Annu. Rep. Med. Chem. (1970) 1969, 285. (5) Hansch,C.,Annu. Rep. Med. Chem. (1967) 1966, 347. (6) Ibid. (1968) 1967, 348. (7) Hansch,C.,Proc. Int.Pharmacol.Meet., 3rd (1968) 7, 141-167. (8) Purcell, W. P., Clayton, J. M., Annu. Rep. Med. Chem. (1969) 1968, 314. (9) Crum-Brown, Α., Fraser, T., Trans. Roy. Soc. Edinburgh (1868-69) 25, 151. (10) Richet, M.C.,C.R. Soc. Biol. (1893) 45, 775. (11) Meyer, H., Arch. Exp.Pathol.Pharmakol. (1899) 42, 109. (12) Meyer, K. H., Hemmi, H., Biochem. Z. (1935) 277, 39. (13) Overton, Ε., Z. Physiol. Chem. (1897) 22, 189. (14) Overton, E., Vierteljahresschr. Naturforsch. Ges. Zuerich (1899) 44, 88. (15) Overton, E., "Studien uber die Narkose," p. 45, Fischer, Jena, Germany, 1901. (16) Fühner, H., Arch. Exp. Pathol. Pharmakol. (1904) 51, 1. (17) Ibid., p. 69. (18) Traube, J., Arch. Ges. Physiol. (Pflügers) (1904) 105, 541. (19) Warburgh, O., Biochem. Z. (1921) 119, 134. (20) Moore, W., J. Agr. Res. (1917) 9, 371. (21) Ibid. (1917) 10, 365.

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