A Computerized Approach to Quantitative Biochemical

2

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 19, 2016 | http://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch002

A Computerized Approach to Quantitative Biochemical Structure-Activity Relationships CORWIN HANSCH Pomona College, Claremont, Calif. 91711

A general approach to the computerization of quantitative biomedical—chemical structure—activity studies is discussed. There are two main problems to consider. One is the formulation of quantitative relationships using physicochemical parameters and regression analysis. As such equations are derived, the problem of organization of the mass of data must be solved. The most suitable, relatively inexpensive method for dealing with the structures of organic compounds via computers is the Wiswesser Line Notation method. This notation and the proper computer program can be of great help in comparative pharmacodynamics.

" D i o c h e m i c a l structure—activity studies i n m e d i c i n a l c h e m i s t r y , a g r i c u l t u r a l c h e m i s t r y , a n d e n z y m o l o g y c o n t i n u e to p r o d u c e a flood of n e w papers e a c h year w h i c h , w h e n p l a c e d o n the m o u n t a i n of s u c h research p u b l i s h e d over the last 70 years, defies o r g a n i z a t i o n .

I n c e r t a i n areas

s u c h as a n t i m a l a r i a l s , anticancer d r u g s , a n d anticholinesterase c o m p o u n d s , so m a n y molecules h a v e b e e n m a d e a n d tested that n o single m i n d c a n encompass

the data m u c h less integrate i t into m e a n i n g f u l s t r u c t u r e -

a c t i v i t y patterns. T h e a w f u l job f a c i n g the d r u g designer once a n active m o l e c u l e has b e e n u n c o v e r e d c a n b e i l l u s t r a t e d w i t h the g e n e r a l f o r m u l a I. COOR

I

(CHY) „

20

Van Valkenburg; Biological Correlations—The Hansch Approach Advances in Chemistry; American Chemical Society: Washington, DC, 1974.

2.

HANSCH

A Computerized

Approach

to

21

Structure-Activity

A s s u m e that a m e m b e r of the a b o v e f a m i l y has b e e n f o u n d to h a v e some d e s i r a b l e a c t i v i t y . I n p l a n n i n g a d r u g m o d i f i c a t i o n s t u d y , let us c o n s i d e r the f o l l o w i n g set of functions for s u b s t i t u t i o n at the seven r i n g positions of n a p h t h a l e n e . Table I.


Function H F Cl Br I Me Et Pr Amyl Hexyl i-Fr i-Bu t-Bu i-Amyl Cyclopropyl Cyclohexyl

C6H5 CH2C6H5

C=CH CF CCI CN OH OMe OEt 3

3

α 6

Electronic and Hydrophobic Substituent τ" 0.00 0.14 0.71 0.86 1.12 0.50 1.00 1.50 2.50 3.00 1.30 1.80 1.68 2.30 1.20 2.51" 2.13 2.01 0.40 0.88 0.79 -0.57 -0.67 -0.02 0.48

σ

ρ

0.00 0.06 0.23 0.23 0.18 -0.17 -0.15 -0.13 -0.13 -0.13 -0.15 -0.13 -0.20 -0.13 -0.21 -0.15 -0.01 -0.09 0.23 0.54 0.33 0.66 -0.37 -0.27 -0.27

Constants

Function

6

5

2

5

2

2

2

3

3

2

SC6H5

3

NH NHCH N(CH ) N (Et), N(Bu) NHC.H, NHCOCH NHCOC H NHCONH N = NC H N0 Si(CH ) 2

3

3

2

2

3

e

6

5 2

5

2

3

-0.27 -0.03

1.48 2.08 -1.05 -0.64 0.39 0.61 1.11 1.23 -1.82 -1.63 1.44 0.55 2.34 -1.23 -0.47 0.18 2.18 4.18 1,37 -0.97 0.49 -1.31 1.69 -0.28 2.59

OBu OC H OCONH OCOCH3 SH SMe SEt SF S0 NH S0 CH SCF S0 CF

3

0.31 0.15 0.00 0.00 0.68 0.57 0.72 0.50 0.93 -0.66 0.84 -0.83 -0.83 -0.83 -0.40 0.00 -0.25 0.24 0.39 0.78 -0.07

χ-values are from the benzene system except where noted. These values are from the phenoxyacetic acid system.

T h e set of 50 functions of T a b l e I is b y n o means extensive.

However,

it does p r o v i d e some examples for c o n s i d e r a t i o n . F o r instance, n o hetero c y c l i c functions h a v e b e e n i n c l u d e d , n o r h a v e w e

considered varying

functions o n the functions—e.g., n i t r o p h e n y l , c h l o r o p h e n y l , etc.

Anyone

c o u l d q u i c k l y extend the list to several h u n d r e d . Just to m a k e a l l of the m o n o f u n c t i o n a l d e r i v a t i v e s at e a c h p o s i t i o n w o u l d m e a n 7 X

50 or 350

possible structures. I f w e c o n s i d e r p o l y f u n c t i o n a l d e r i v a t i v e s , the n u m bers increase r a p i d l y a c c o r d i n g to the f o r m u l a X

A

w h e r e X is the n u m b e r

of functions a n d Ν is the n u m b e r of positions. T h e f o r m u l a h o l d s o n l y as l o n g as no elements of s y m m e t r y are i n t r o d u c e d . T h e f o l l o w i n g c a l c u lations illustrate the a w e s o m e p o s s i b i l i t i e s for a set of o n l y 50 functions for substitutions i n 2, 3, 4, 6, a n d 7 of the possible r i n g positions.


22

BIOLOGICAL CORRELATIONS

50

2

=

2500

50

3

=

125,000

50

4

=

6,250,000

50

6

=

312,500,000

50

7

=

15,625,000,000

T H E HANSCH A P P R O A C H


O f course, to this m u s t be a d d e d the possibilities r e s u l t i n g f r o m v a r i a t i o n s i n Y , n, a n d R.

T a k e the case w h e r e w e v a r y substituents at o n l y f o u r

positions o n the r i n g b u t , i n a d d i t i o n , w e m a k e 10 changes i n Y , 10 i n R, a n d f o u r i n n . T h i s leads t o : 5 0

4

X 10 X 10 X 4 =

2,500,000,000.

With

the r e l a t i v e l y s i m p l e l i m i t s set above, the c h e m i s t faces a staggering p r o b l e m of selection. T h e p r o b l e m becomes m u c h worse i f w e e n t e r t a i n the p o s s i b i l i t y of i n t r o d u c i n g 1, 2, or 3 heteroatoms into the r i n g .

Having

so little i n the w a y of t h e o r y for g u i d a n c e , the s i m p l e w a y out is u s u a l l y f o l l o w e d , a n d one makes the c o m p o u n d s w h i c h are easiest to synthesize. W h i l e the cost of synthesis is a n aspect of d r u g research w h i c h cannot be t a k e n l i g h t l y , w i t h the great advances i n m o d e r n s y n t h e t i c t e c h n i q u e s quite c o m p l e x structures c a n b e m a d e i f there is g o o d reason to d o so. H o p e f u l l y , c o m p u t e r techniques c a n b e d e v e l o p e d to h e l p w i t h the d e c i s i o n m a k i n g i n d r u g d e s i g n as w e l l as o r g a n i z a t i o n of the literature. T h e t w o major aspects of the p r o b l e m are d i a g r a m m e d i n F i g u r e 1. Wiswesser L i n e N o t a t i o n Structure : Data Bank of D r u g Information

Chemical Abstracts Connection Tables

-* H a m m e t t T y p e P a r a m e t e r s ^

D y n a m i c s ——> M . O. P a r a m e t e r s de novo P a r a m e t e r s

Figure 1. The

Model for computerization

c o m p u t e r i z a t i o n of

attention.

of structure-activity

o r g a n i c structures has r e c e i v e d

relationships considerable

T w o g e n e r a l approaches represented b y the W i s w e s s e r l i n e

n o t a t i o n a n d c o n n e c t i o n table storage h a v e r e c e i v e d the most attention. N e i t h e r system has r e a c h e d a state of p e r f e c t i o n .

B o t h h a v e advantages

a n d disadvantages. T h e W i s w e s s e r ( I ) system is m u c h less expensive i n terms of c o m p u t e r storage space a n d search t i m e . F o r these reasons w e h a v e elected to e x p e r i m e n t w i t h this m e t h o d for o r g a n i z i n g d r u g f o r m u las. W h i l e p r o f i c i e n c y i n w r i t i n g this l a n g u a g e r e q u i r e s l e a r n i n g a large n u m b e r of rules, l e a r n i n g to r e a d the n o t a t i o n is r e l a t i v e l y s i m p l e . f o r m u l a for p h e n y l a l a n i n e is w r i t t e n as f o l l o w s :


The

2.

A Computerized

HANSCH

Approach

to

ο II

y

•

CH CHC—OH s 2

QVYZIR

I

NH

2

T h e t w o - d i m e n s i o n a l s t r u c t u r a l f o r m u l a reduces symbols easily p u n c h e d o n a n I B M c a r d . Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 19, 2016 | http://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch002

23

ι

x

Il

Structure-Activity

to a l i n e a r set of six

Q represents O H , V is the

Ο s y m b o l for — C — , Y indicates a b r a n c h e d c h a i n to w h i c h a n a m i n o f u n c t i o n ( Ζ ) a n d a C H g r o u p ( 1 ) are attached. Β stands for the benzene 2

r i n g a t t a c h e d to the m e t h y l e n e f u n c t i o n . N o t o n l y does s u c h a f o r m u l a r e q u i r e l i t t l e storage space, b u t it makes substructure s e a r c h i n g r e l a t i v e l y easy. F o r e x a m p l e , one c a n q u e r y the d a t a b a n k for a l l c o m p o u n d s

hav-

O

II

i n g the g r o u p i n g Z V O (i.e., H N C O - ) . 2

S y s t e m + Χ , · — d r u g —» P e r t u r b a t i o n ^

(1)

P e r t u r b a t i o n ^ = / ( P h y s i c o c h e m i c a l parameters of X y )

(2)

t

Parameters Hydrophobic :

log Ρ or χ

Electronic:

σ, σ+, σ~, σ*, Μ . Ο . ,

Steric :

Ε , molar volume, molecular refractivity

ρΚ

α

8

F o r a d e f i n i t i o n of these parameters, see R e f . 3. A l t h o u g h it is the d y n a m i c s of structure—activity studies w i t h w h i c h we

are most

concerned

w e l l integrated.

at present, structure a n d d y n a m i c s m u s t

be

T h e a b o v e scheme represents o u r present m o d e l

for

c o m p u t e r i z i n g the d y n a m i c aspects of s t r u c t u r a l m o d i f i c a t i o n . T h e t e r m system refers to the test system u s e d , be i t a mouse, a n organelle, or a n i s o l a t e d e n z y m e . E q u a t i o n 1 is l i k e a n y c h e m i c a l e q u a t i o n i n that a g i v e n system +

a

reactant y i e l d s a p r o d u c t .

H o w e v e r , i n d r u g research one

does not isolate the p r o d u c t ; i n s t e a d , i t is c h a r a c t e r i z e d b y a n o b s e r v e d s t a n d a r d response ( P e r t u r b a t i o n ^ ) . I n E q u a t i o n 1 i t is a s s u m e d that a l l of the drugs X ^ - d r u g are a c t i n g i n the same w a y b y the same m e c h a n i s m i n p r o d u c i n g the o b s e r v e d p e r t u r b a t i o n . P e r t u r b a t i o n ^ is p r o b a b l y best defined i n terms of l o g 1 / C w h e r e C is the m o l a r concentration of d r u g p r o d u c i n g the s t a n d a r d response i n a fixed u n i t of t i m e . O n e hopes to r a t i o n a l i z e the p e r t u r b a t i o n w i t h one or m o r e i n d e p e n d e n t v a r i a b l e s


24



Table II. Type of Compound

Biological

Alcohols and ketones ROH


(Equation

2).

1/C

Activity

I o indophenol oxidation by rabbit kidney 5

D r o p i n b l a c k l i p i d m e m b r a n e resistance f r o m 1 0 to 10 o h m / c m —10 m v change i n rest p o t e n t i a l of lobster a x o n — 5 m v change i n rest p o t e n t i a l of lobster axon 1 0 0 % i n h i b i t i o n frog heart I o red b l o o d cell oxygen c o n s u m p t i o n I n h i b i t i o n b a c t e r i a l luminescence M i n i m u m i n h i b i t i o n c o n c e n t r a t i o n frog sciatic nerve N a r c o s i s of goldfish I o tortoise heart C o l c h i c i n e - l i k e m i t o s i s i n onion root t i p N a r c o s i s of barnacle l a r v a e N a r c o s i s of 2.5-day tadpoles N a r c o s i s of 12-day tadpoles I o guinea p i g i l e u m 1 0 0 % i n h i b i t i o n tadpole m o v e m e n t N a r c o s i s of 83-day tadpoles 8

ROH ROH Miscellaneous Miscellaneous ROH ROH ROH ROH Miscellaneous ROH ROH ROH ROH Miscellaneous ROH

Log

6

2

5

5

5

Some of the c o m m o n l y u s e d v a r i a b l e s are i n d i c a t e d

the scheme above. A t this v e r y early stage i n the d e v e l o p m e n t of m a t h e m a t i c a l s t r u c t u r e - a c t i v i t y w o r k a c o m p l e t e set of w e l l u n d e r s t o o d p a r a m e ters has not b e e n d e v e l o p e d ; h o w e v e r , the set a b o v e has at least a l l o w e d us to start serious w o r k .

T h e greatest l a c k at present is f o r a suitable

n u m e r i c a l w a y to define the geometry of o r g a n i c c o m p o u n d s — i . e . , one that does not r e q u i r e a n i n o r d i n a t e n u m b e r of terms. The

development

of

such

extrathermodynamic

equations

places

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 i n a f o r m easily stored a n d m a n i p u l a t e d b y computers.

M a n y s u c h examples h a v e b e e n p u b l i s h e d (2, 3 ) a n d , at

present, w e are e x p e r i m e n t i n g w i t h a g r o u p of a b o u t 1000 s u c h equations w h i c h correlate about 15,000 o r g a n i c structures.

C o r r e l a t i o n equations

n o w c o v e r systems r a n g i n g f r o m s i m p l e proteins (4)

to p u r e

( 5 ) , antibodies ( 6 ) , organelles ( 7 ) , a n d w h o l e a n i m a l s ( 8 ) . b a n k of s u c h equations grows, specific i n f o r m a t i o n o n m a n y accrues.

enzymes

A s the d a t a compounds

T o g a i n the m a x i m u m use of this i n f o r m a t i o n , the t w o systems

of F i g u r e 1 m u s t be c o m p l e t e l y i n t e r a c t i v e . T h e f o l l o w i n g are examples of t y p i c a l queries one w o u l d l i k e to m a k e of s u c h a system via a remote t e r m i n a l i n the d r u g d e s i g n e r s l a b o r a t o r y . Ο

II ( 1 ) L i s t a l l d r u g s c o n t a i n i n g the f u n c t i o n — S C N H i n o r d e r first of i n c r e a s i n g l o g 1 / C a n d t h e n i n o r d e r of l o g P . L i s t t h e system i n w h i c h e a c h is active a n d the t y p e of a c t i o n m e a s u r e d . 2


2.

— a log Ρ +


A Computerized

HANSCH

Approach

to

25

Structure-Activity

b Equation

r

s

8

0.993

0.064

3

-0.52=1= .40

7

0.986

0.248

4

- 0 . 2 3 ± . 18 -0.09±.13 0.11=1=.12 0.12=fc.l5 0.22±.12 0.27=1= .20 0.34±.ll 0.52±.13 Q.52±.23 0.57d=.ll 0.59=b.l7 0.61=1=.13 0.62=i=.14 0.60=1=. 11 0.63=1=.11

5 5 28 14 8 8 8 10 19 14 8 8 8 16 8

0.991 0.995 0.975 0.977 0.998 0.995 0.985 0.972 0.963 0.991 0.997 0.998 0.997 0.994 0.998

0.112 0.082 0.182 0.214 0.100 0.141 0.106 0.136 0.340 0.140 0.141 0.109 0.113 0.137 0.095

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

a

b

0.90db.ll

-0.55=1= .06

1.26=1= .24 0.90=b.22 0.86=1=.16 0.93±.08 0.92=1=.12 1.17=fc.08 1.05=1=.10 1.15=L.20 0.99=1=.20 0.96±.14 1.05±.09 1.31=1=.11 1.24=1= .08 1.06=1= .08 1.22=1= .07 1.20=b.07

η

( 2 ) L i s t a l l equations of the t y p e : l o g 1 / C = a l o g Ρ + bE + c. O r d e r t h e m first a c c o r d i n g to i n c r e a s i n g values of a a n d t h e n a c c o r d i n g to i n c r e a s i n g values of b. L i s t t h e system a n d t y p e of p e r t u r b a t i o n for each equation. 8

( 3 ) L i s t a l l equations h a v i n g l o g P values i n the r a n g e 4 - 5 for drugs a c t i n g o n chloroplasts. 0

(4)

L i s t a l l d r u g s c o n t a i n i n g the f u n c t i o n

h a v i n g l o g 1 / C values > 5 . 0

a n d a c t i v i t y against v i r u s .

( 5 ) L i s t a l l equations c o r r e l a t i n g the a c t i o n of a r o m a t i c amines or phenols w h i c h c o n t a i n a t e r m i n σ". O r d e r these a l p h a b e t i c a l l y b y system. ( 6 ) L i s t the systems p e r t u r b e d b y a l l amides l o g Ρ values of 2 ± .5.

( C O N H ) having 2

T h e a b o v e queries are o n l y a f e w of the scores w h i c h one c a n r e a d i l y i m a g i n e to be of v a l u e i n a t r u l y c o m p r e h e n s i v e 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 system.

I n a d d i t i o n to structure—activity equations c o r r e l a t i n g

b i o c h e m i c a l systems i t is i m p o r t a n t to i n c l u d e i n the d a t a b a n k as m a n y examples as possible of substituent effects i n h o m o g e n e o u s o r g a n i c r e a c -


26



tions w h i c h c a n be u s e d as standards of c o m p a r i s o n for

biochemical

processes. A l t h o u g h w e h a v e not c o m p l e t e d a l l of the c o m p u t e r p r o g r a m m i n g n e e d e d to a n s w e r a l l of the a b o v e questions, the d y n a m i c p a r t of the system i n F i g u r e 1 is m o r e

or less i n o p e r a t i o n .

Some

the k i n d of questions w h i c h c a n b e u s e d to f o r m u l a t e a pharmacodynamics

can now be

examples

considered.

T a b l e s I I a n d I I I list equations w h i c h r e s u l t e d f r o m the Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 19, 2016 | http://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch002

of

comparative present

d a t a b a n k f r o m the f o l l o w i n g q u e r y : list a l l equations l i n e a r i n l o g Ρ w h e r e a c t i v i t y is defined as l o g 1 / C h a v i n g intercepts < 1 a n d h a v i n g at least five d a t a points p e r set. c l u s i o n (9)

S t u d y of this p r i n t - o u t y i e l d e d the c o n

that the equations of this t y p e n o w i n h a n d f e l l i n t o t w o

major classes: those of T a b l e I I w i t h slopes of m e a n a n d s t a n d a r d d e v i a t i o n of 1.07 ±

.14 a n d those of T a b l e I I I w i t h slopes of 0.74 ±

.09.

The

equations w e r e d i v i d e d i n t o t h e t w o sets solely o n the basis of

slope

w i t h o u t r e g a r d to the k i n d of b i o l o g i c a l a c t i o n i n v o l v e d . It w o u l d seem that a l l of the b i o l o g i c a l processes of T a b l e I I m i g h t be b r o u g h t

about

b y m e m b r a n e p e r t u r b a t i o n . C o m p a r i s o n of the equations of T a b l e I I w i t h the f o l l o w i n g average e q u a t i o n

(10)

for hemolysis lends c r e d e n c e to

this h y p o t h e s i s : log 1 / C = 0.93db.l7 log Ρ -

0.09±.23

(18)

T h e slope of E q u a t i o n 18 is the m e a n v a l u e for 15 different sets of drugs ( i o n i c a n d n o n i o n i c ) c a u s i n g hemolysis. T h e intercept is the m e a n v a l u e f r o m seven sets of neutral

d r u g s c a u s i n g hemolysis. Table III.

Type of Compound ROH ROH ROH Miscellaneous Miscellaneous Miscellaneous Miscellaneous Phenols Miscellaneous ROH Miscellaneous Miscellaneous Phenols Anilines

Biological

Log

Activity

D e n a t u r a t i o n horse heart c y t o c h r o m e D e n a t u r a t i o n whale m y o g l o b i n Denaturation a-chymotrypsinogen P r e c i p i t a t i o n sheep l i v e r nucleoprotein at 4 0 ° C i n 30 m i n u t e s 1 0 0 % i n h i b i t i o n b o v i n e muscle succinate oxidase 1 0 0 % i n h i b i t i o n sheep l i v e r succinate oxidase P r e c i p i t a t i o n sheep l i v e r n u c l e o p r o t e i n at 40°C i n 15 m i n u t e s G r o w t h i n h i b i t i o n M. tuberculosis 1 5 - 2 0 % i n h i b i t i o n b o v i n e muscle succinate oxidase G r o w t h i n h i b i t i o n S. aureus 1 5 - 2 0 % i n h i b i t i o n sheep l i v e r succinate oxidase I n h i b i t i o n fibrin s w e l l i n g C o n v e r s i o n of c y t o c h r o m e P-450 to P-420 C o n v e r s i o n of c y t o c h r o m e P-450 to P-420


1/C

2.

A Computerized

HANSCH

Approach

to

27

Structure-Activity

T h e m e a n slope for the 17 examples of T a b l e I I is 1.07 ±

.14.

The

equations h a v e b e e n o r d e r e d w i t h respect to intercept w i t h a n o v e r a l l difference i n this p a r a m e t e r of about 1 l o g u n i t .

T h u s , narcosis of t a d

poles requires about one-tenth l o w e r c o n c e n t r a t i o n of d r u g t h a n the 5 0 % i n h i b i t i o n of i n d o p h e n o l oxidase ( E q u a t i o n 3 ). T h e e q u a t i o n most n e a r l y r e s e m b l i n g the m o d e l e q u a t i o n ( E q u a t i o n 18) is E q u a t i o n 6 c o r r e l a t i n g the structure—activity r e l a t i o n s h i p b e t w e e n

the c o n c e n t r a t i o n of

ROH


necessary to p r o d u c e a 5-mv c h a n g e i n the rest p o t e n t i a l of the lobster axon.

T h i s close r e l a t i o n s h i p b e t w e e n h e m o l y s i s a n d n e r v e

membrane

p e r t u r b a t i o n has b e e n n o t e d b y others u s i n g different t e c h n i q u e s T h e r e l a t i o n s h i p s of T a b l e I I s h o w that different sets of

12).

(II,

molecules

a c t i n g o n v e r y different systems c a n be c o m p a r e d q u i c k l y i n n u m e r i c a l terms. S u c h relationships c a n b e u s e f u l i n d e s i g n i n g s y n t h e t i c m e m b r a n e s h a v i n g properties s i m i l a r to n a t u r a l systems.

F o r example, E q u a t i o n 4

correlates the change i n resistance caused b y alcohols o n p o t a s s i u m i o n p e r m e a b i l i t y of b l a c k l i p i d m e m b r a n e

( B L M ) p r e p a r e d f r o m the l i p i d

of sheep erythrocytes. T h e rather large negative intercept of E q u a t i o n 4 indicates t h a t three times the c o n c e n t r a t i o n of i s o l i p o p h i l i c a l c o h o l is needed

to change

hemolysis.

the resistance of the B L M as is n e e d e d

to

cause

A l t h o u g h the t w o processes are q u i t e different, the role of

h y d r o p h o b i c forces i n each c a n be

compared.

T h e intercept of the equations is o p e n to m o r e v a r i a t i o n t h a n the slope.

T h e v a l u e of the i n t e r c e p t w i l l d e p e n d o n the s e n s i t i v i t y of the

system a n d the degree of response d e m a n d e d b y the investigator =

a log Ρ +

(e.g.,

b r

s

Equation

a

b

η

0.52±.10 0.84 ± . 19 0.70=fc.l4 0.82=fc.ll

-0.76±.04 -0.58±.10 -0.45±.07 -0.26±.10

5 7 8 13

0.995 0.982 0.982 0.979

0.026 0.089 0.071 0.132

20 21 22 23

0.75=b.l5 0.76±.14 0.80±.13

-0.22±.16 -0.19±.15 -0.17±.12

14 14 14

0.951 0.957 0.970

0.205 0.194 0.132

24 25 26

0.78=L.06 0.77±.12 0.65±.12 0.80±.14 0.86=fc.32 0.57=b.08 0.66±.15

-0.09±.27 0.05±.12 0.06±.08 0.10±.15 0.21±.31 0.36±.19 0.36=L.21

14 14 9 14 8 13 7

0.992 0.970 0.979 0.962 0.971 0.979 0.981

0.133 0.162 0.089 0.191 0.224 0.132 0.087

27 28 29 30 31 32 33


28


EDioo, E D a n d 6.

5 0

, etc.).


T h i s effect c a n b e seen b y c o m p a r i n g E q u a t i o n s 5

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

is

needed

to p r o d u c e a 10-mv c h a n g e as is n e e d e d to p r o d u c e a 5-mv c h a n g e i n the rest p o t e n t i a l of the nerve. A s i m i l a r effect is a p p a r e n t i n E q u a t i o n s 7 a n d 12. H o w e v e r , t w o different k i n d s of hearts are i n v o l v e d here, a n d the difference m a y i n p a r t be the result of the different types of tissue. T h e slopes a n d intercepts of E q u a t i o n s 8 a n d 9 are q u i t e close, i n d i Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 19, 2016 | http://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch002

c a t i n g that the m o l e c u l a r probes i n h i b i t i n g the t w o s u p e r f i c i a l l y different processes are p r o b a b l y o p e r a t i n g i n the same w a y at the m o l e c u l a r l e v e l . I n h i b i t i o n of l u m i n e s c e n c e appears to b e different f r o m i n h i b i t i o n

of

b a c t e r i a l g r o w t h ( c o m p a r e E q u a t i o n 9 w i t h E q u a t i o n s 27 a n d 2 9 ) .

In

various p u b l i s h e d (13)

a n d u n p u b l i s h e d results l i n e a r r e l a t i o n s h i p s w i t h

slopes of a b o u t 0.7 for the i n h i b i t i o n of b a c t e r i a l g r o w t h h a v e b e e n f o u n d . E q u a t i o n 13 correlates a m i x e d set of c o m p o u n d s w h i c h p r o d u c e a n a b n o r m a l t y p e of mitosis r e s e m b l i n g that c a u s e d b y c o l c h i c i n e . T h e role of h y d r o p h o b i c forces c a u s i n g this k i n d of m i t o t i c a c t i v i t y is closely r e l a t e d to that c a u s i n g h e m o l y s i s ( E q u a t i o n 1 8 ) , i n h i b i t i n g q u i n e a p i g ileum (Equation 17), I

5 0

r e d b l o o d c e l l o x y g e n c o n s u m p t i o n , etc.

The

results of T a b l e I I i n d i c a t e t h a t E q u a t i o n 18 c a n b e u s e d as a m o d e l for nonspecific m e m b r a n e p e r t u r b a t i o n i n v a r i o u s systems. I n T a b l e I I I a different set of l i n e a r equations has b e e n T h e m e a n slope f o r the 14 examples is 0.74 ±

grouped.

.09. T h e m o l e c u l a r probes

u s e d to o b t a i n these equations i n d i c a t e a s i g n i f i c a n t l y different d e p e n d ence of b i o l o g i c a l response o n l o g P . T h i s m e a n slope is closer to that f o u n d for the b i n d i n g of o r g a n i c c o m p o u n d s b y proteins (14).

I n fact,

except for E q u a t i o n s 27 a n d 29, m o r e or less i s o l a t e d proteins constitute the b i o l o g i c a l systems of T a b l e I I I .

T h e s e systems are no d o u b t

less

l i p o p h i l i c t h a n the m e m b r a n e s of r e d b l o o d cells or nerve cells w h i c h b o t h c o n t a i n 5 0 % or m o r e l i p i d s . O f course, t h e highest concentrations ( l o w e s t i n t e r c e p t s ) of i s o l i p o p h i l i c molecules are r e q u i r e d for the p r o c esses i n v o l v i n g extensive d e n a t u r a t i o n or 1 0 0 % e n z y m i c i n h i b i t i o n ( E q u a tions 2 0 - 2 6 ) . E x a m p l e s s h o w i n g the r e l a t i o n s h i p b e t w e e n the v a l u e of the i n t e r cept a n d the degree of response c a n be seen b y c o m p a r i n g E q u a t i o n s 24 a n d 25 w i t h 28 a n d 30. T h e differences i n the t w o sets of intercepts are 0.27 a n d 0.29, i n d i c a t i n g that a t w o f o l d increase i n c o n c e n t r a t i o n is r e q u i r e d to cause 1 0 0 %

i n h i b i t i o n of succinate oxidase over

15-20%

inhibition. E q u a t i o n s 32 a n d 33 h a v e b e e n p l a c e d o n a l o g Ρ basis a n d are therefore different f r o m those p u b l i s h e d b y I c h i k a w a a n d Y a m a n o

(15).

I n this s t u d y u s i n g r a t l i v e r m i c r o s o m e c y t o c h r o m e P-450, there is l i t t l e difference b e t w e e n the slopes or intercepts for the t w o different sets of congeners.

I n fact, a single e q u a t i o n c o u l d b e u s e d to correlate the 21


2.

HANSCH

compounds.

A Computerized

Approach

to

29

Structure-Activity

T h i s indicates that h y d r o p h o b i c

forces alone

(as

opera

t i o n a l l y defined b y l o g P ) p r o m o t e t h e c o n v e r s i o n of P-450 —> P-420. E q u a t i o n s 27 a n d 29 are v e r y m u c h l i k e E q u a t i o n s 32 a n d 33, s u g gesting that p e r t u r b a t i o n of the o x i d a t i v e e n z y m e systems m a y be r e sponsible for g r o w t h i n h i b i t i o n of the b a c t e r i a . I n s u m m a r y , the equations of T a b l e s I I a n d I I I b e g i n to sort out t w o g e n e r a l types of systems, each of w h i c h d i s p l a y s a different k i n d of Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 19, 2016 | http://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch002

nonspecific response to l i p o p h i l i c m o l e c u l a r probes. T h e larger the v a l u e of the intercept, the m o r e

sensitive is the

system or the m o r e specific the p h a r m a c o p h o r i c f u n c t i o n of the set of congeners.

T h e f o l l o w i n g set of three equations w a s selected for the

d a t a b a n k to i l l u s t r a t e h o w m o r e sensitive processes c a n be

compared

via e x t r a t h e r m o d y n a m i c correlations. 1 - t o - l B i n d i n g of M i s c e l l a n e o u s C o m p o u n d s b y B o v i n e H e m o g l o b i n log 1 / C = 0 . 7 1 ( ± . 1 3 ) l o g Ρ +

1.51(±.33)

n 17

(16)

r s 0.950 0.160

(34)

I o of H y d r o x y i n d o l e - O - M e t h y t r a n s f e r a s e b y J V - A c y l t r y p t a m i n e A m i n e s (17) n r s log 1 / C = 0 . 6 0 ( d b . l O ) l o g P + 1 . 4 9 ( ± . 4 2 ) 21 0.948 0.170 (35) 5

7 5 % I n h i b i t i o n of M u l t i p l i c a t i o n of I n f l u e n z a B . V i r u s b y B e n z i m i d a z o l e s log 1 / C = 0 . 5 8 ( ± . 1 7 ) l o g P +

1.58(±.46)

n 15

r s 0.903 0.210

(36)

W h i l e the a b o v e three examples w e r e p i c k e d because of t h e i r s i m i l a r i t y i n b o t h slope a n d intercept, t h e y are not necessarily i d e n t i c a l p r o c esses at the m o l e c u l a r l e v e l . H o w e v e r , they m u s t be q u i t e s i m i l a r . W h i l e it is k n o w n that i n E q u a t i o n 34 one m o l e c u l e of substrate is b o u n d to one m o l e c u l e of p r o t e i n , this is not k n o w n to be the case for E q u a t i o n s 35 a n d 36. T h e r e is a fair p r o b a b i l i t y that this is true for E q u a t i o n 35. T h e parameters i n E q u a t i o n 35 are s l i g h t l y different f r o m those d e r i v e d b y L i e n , H u s s a i n , a n d T o n g (17)

because of slight differences i n l o g Ρ

values. T h e slopes of the a b o v e three equations are 0.6 ±

.1. S u c h values

are c o m m o n l y o b s e r v e d for nonspecific b i n d i n g of o r g a n i c c o m p o u n d s

by

a v a r i e t y of proteins a n d proteinaceous m a t e r i a l ( 3 , 1 4 ) . U s i n g E q u a t i o n s 34 a n d 35 as points of reference, some f e e l i n g a b o u t t h e i n h i b i t i o n of virus by benzimidazoles can be formed.

E q u a t i o n 36 has b e e n f o r m u

l a t e d f r o m the d a t a i n T a b l e I V . C o m p a r i s o n of intercepts shows t h a t this is not a v e r y specific i n h i b i t o r y process.

It w o u l d be i n t e r e s t i n g to

k n o w h o w m a n y b e n z i m i d a z o l e s are b o u n d p e r v i r u s s u b u n i t so that a better c o m p a r i s o n w i t h E q u a t i o n 34 c o u l d b e m a d e .


30


Table IV.

75%

T H E HANSCH APPROACH

Inhibition Influenza B. Virus by

Benzimidazoles


log 1/C Compound

log P

1-Methyl Benzimidazole 2-Methyl 5-Methyl 5,6-Dimethyl 4,6-Dimethyl 2,5-Dimethyl 4,5-Dimethyl 2,4,6-Trimethyl 2,4,5-Trimethyl 5,6-Diethyl 2-Propyl-5-methyl 2,4,5,6,7-Pentamethyl 2-Ethyl,5-methyl 2-Butyl,5-methyl 2-Propyl,5-methyl

1.84 1.34 1.84 1.84 2.34 2.34 2.34 2.34 2.84 2.84 3.34 3.34 3.84 2.84 3.84 3.14

obsd.

b

a

2.14 2.46 2.51 2.72 2.72 2.82 2.89 2.96 3.05 3.20 3.39 3.60 3.66 3.74 3.77 3.77

c

calcd.

\Mog 1/C\

2.65 2.36 2.65 2.65 2.94 2.94 2.94 2.94 3.24 3.24 3.53 3.53 3.82 3.24 3.82 3.41

0.51 0.10 0.14 0.07 0.22 0.12 0.05 0.02 0.19 0.04 0.14 0.07 0.16 0.50 0.05 0.36

Based on the value of 1.34 for benzimidazole. The value of 0.5 was added to this parent compound for each C H or C H to obtain other log Ρ values. This point omitted since it is the only N-methyl derivative and it is a poor fit. a

b

3

2

c

I n p e r u s i n g o u r present d a t a b a n k for equations l i n e a r i n l o g Ρ w i t h h i g h e r intercepts one finds that the h y p n o t i c drugs m a k e a n i n t e r e s t i n g g r o u p for c o m p a r i s o n .

E q u a t i o n s 37 a n d 38 are d e r i v e d f r o m the d a t a

in Tables V and V I . M i n i m u m H y p n o t i c D o s e i n M o u s e of J V , i V - A l k y l a r y l u r e a s (19) n log 1 / C = 0 . 5 3 ( ± . 0 8 ) l o g Ρ +

2.44(=b.l0)

27

M i n i m u m H y p n o t i c D o s e i n R a t of 5 , 5 - B a r b i t u r a t e s log 1 / C = 0.57(=b.21)log Ρ +

2.44(db.40)

n 15

r

s

0.945 0.108

(37)

(21) r 0.851

s 0.156

(38)

T h e great s i m i l a r i t y of E q u a t i o n s 37 a n d 38 h i g h l i g h t s the c o m m o n m e c h a n i s m of a c t i o n of t w o s u p e r f i c i a l l y different types of amides.

I n each

of the a b o v e examples, c o m p o u n d s h a v i n g l o g Ρ values b e l o w the o p t i m u m of l o g P

0

w e r e s t u d i e d . H e n c e , a d d i t i o n of a t e r m i n ( l o g P )

not result i n a n i m p r o v e d

c o r r e l a t i o n i n either case.

The

2

did

confidence

intervals o n the intercepts of E q u a t i o n s 37 a n d 38 are t i g h t e r t h a n those o n eight sets of p a r a b o l i c equations c o r r e l a t i n g h y p n o t i c a c t i v i t y of b a r biturates i n a v a r i e t y of a n i m a l s (22). equations w i t h m o d e r a t e l y

H o w e v e r , for six of the p a r a b o l i c

g o o d confidence i n t e r v a l s , a m e a n


intercept

2.

A Computerized

HANSCH

Approach

to

31

Structure-Activity

of 2.1 =t .3 is f o u n d . T h e agreement w i t h E q u a t i o n s 37 a n d 38 is q u i t e g o o d , e s p e c i a l l y w h e n one considers that the e x p e r i m e n t a l c o n d i t i o n s a n d the t y p e of a n i m a l s u s e d w e r e q u i t e v a r i e d . T h e intercepts

(22)

( n u m b e r s u n d e r f o r m u l a s ) f r o m p a r a b o l i c c o r r e l a t i o n equations for the


f o l l o w i n g three types of h y p n o t i c amides are close to those of E q u a t i o n s

2.50(db.67)

0

0

II

11

(CH,) CCONH,

II

0

II

RC—NHCNH—Clt

2

I

SR 1.98(±.54)

1.89(±.10)

III

IV

37 a n d 38. T h e a b o v e examples w i t h h y p n o t i c s i n d i c a t e t h a t n u m e r i c a l comparisons c a n be m a d e w i t h q u i t e different systems i n a general w a y . I n this w a y one gets a v i e w of the forest w i t h o u t b e i n g too

concerned

a b o u t the i n d i v i d u a l trees. H i g h e r intercepts i n d i c a t i n g h i g h e r s e n s i t i v i t y a n d specificity are c o n t a i n e d i n the f o l l o w i n g examples.

K i l l i n g of M. fructicola

spores b y B e n z o q u i n o n e s

(23) n

log 1 / C = 0 . 8 8 ( ± . 4 3 ) l o g P + 3.53(d=.80)

r

s

10

0.859 0.579

(39)

n 15

r 0.941

s 0.136

(40)

r s 0.957 0.222

(41)

I n h i b i t i o n of S. typhosa b y A r o m a t i c A m i n e s (13) log 1 / C = 0 . 5 8 ( = f c . l 2 ) l o g P + 0.97(=b.28)

Ieo C. albicans

(23) b y

|[ XC H HN 6

4

| Ν

log 1 / C = 0.50(d=.15)log Ρ + 4 . 1 5 ( ± . 3 5 )

NHC H X e

n 8

4


32


ED

5 0

T H E HANSCH APPROACH

S. aureus i n M i c e of P h e n o x y p e n i c i l l i n s (21/)

log 1 / C =

-0.46(=b.lO)logP-ion

+ 4.85(±.10)

n 21

r 0.912

s 0.187

E v e n t h o u g h E q u a t i o n 39 is not a v e r y sharp c o r r e l a t i o n

(42)

(probably

b e c a u s e i t is l a c k i n g a s u i t a b l e electronic t e r m ) , i t does serve to i l l u s trate i n i s o l i p o p h i l i c terms the h i g h i n t r i n s i c t o x i c i t y of q u i n o n e s to f u n g i .


C o m p a r i s o n of E q u a t i o n s 40 a n d 41 shows that s i m p l e a r o m a t i c

amines

do not h a v e a h i g h i n t r i n s i c t o x i c i t y . T h u s the p y r i m i d i n e m o i e t y ,

Table V .

Hypnosis of Mice by

when

N,N~Alkylarylureas

a

log 1/C Compound Me Me Me Et Me Me Me Et Me Et Et Me Me Me Et Et Et Et Pr Et Et Pr Bu Pr Pr Bu Bu

Phenyl 4-Anisyl 2-Anisyl Phenyl 2-Tolyl 3-Anisyl 4-EtO-phenyl 4-Anisyl 4-Tolyl 2-Anisyl 4-EtO-phenyl 3-Tolyl 4-EtO-phenyl 2-EtO-phenyl 3-Anisyl 3-Tolyl 2-EtO-phenyl 4-Tolyl Phenyl 2-Tolyl 3-EtO-phenyl 4-Tolyl Phenyl 3-Tolyl 2-Tolyl 4-Tolyl 2-Tolyl a b

log P 0.42 0.42 0.42 0.92 0.92 0.42 0.92 0.92 0.92 0.92 1.42 0.92 0.92 0.92 0.92 1.42 1.42 1.42 1.42 1.42 1.42 1.92 1.92 1.92 1.92 2.42 2.42

b

obsd.

calcd.

\alog 1/C\

2.46 2.62 2.67 2.80 2.82 2.85 2.85 2.87 2.90 2.93 3.00 3.00 3.06 3.09 3.15 3.19 3.19 3.19 3.19 3.26 3.26 3.44 3.48 3.51 3.55 3.60 3.00

2.67 2.67 2.67 2.93 2.93 2.67 2.93 2.93 2.93 2.93 3.20 2.93 2.93 2.93 2.93 3.20 3.20 3.20 3.20 3.20 3.20 3.45 3.47 3.47 3.47 3.73 3.73

0.21 0.05 0.00 0.13 0.11 0.18 0.08 0.06 0.03 0.00 0.20 0.07 0.13 0.16 0.22 0.01 0.01 0.01 0.01 0.06 0.06 0.03 0.01 0.04 0.08 0.13 0.07

From Ref. 19. Log Ρ values based on value of 0.42 for C e B U N - C O N H s .

The O C H

3

group is

CH given a value (20) of 0.00. Substituents in ortho, meta, and para positions are all given same % values. Adding a term in σ for benzene ring substitutuents did not improve the correlation nor did the addition of a term in (log P ) . 3

2


2.

HANSCH

A Computerized

Table V I .

Approach

to

Structure-Activity

Hypnosis of Rats by

5,5-Barbiturates

33 0

log 1/C log P


Compound Et Et Et Et Et Et Et Et Et Et Et Et Et Allyl Allyl Allyl

6

0.65 1.42 2.15 1.95 1.95 1.95 1.95 1.75 1.79 1.65 1.45 1.45 2.45 2.15 2.15 1.99

Et Phenyl Amyl Isoamyl 2-Me-butyl 1-Me-butyl 1-Et-propyl 1,2-Di-me-propyl Cyclopentyl Butyl Isobutyl sec-Butyl 1-Me-amyl 1-Me-butyl 1-Et-propyl Cyclopentyl

obsd.

calcd.

\Mog 1/C\

2.79 3.12 3.45 3.50 3.45 3.81 3.81 3.45 3.45 3.33 3.28 3.63 3.60 3.83 3.77 3.67

2.81 3.25 3.67 3.56 3.56 3.56 3.56 3.44 3.45 3.39 3.27 3.27 3.84 3.67 3.67 3.58

0.02 0.13 0.22 0.06 0.11 0.25 0.25 0.00 0.00 0.06 0.01 0.36 0.24 0.16 0.10 0.09

e

" F r o m Réf. 21. See Réf. 22 for experimental and calculated values. This data point not used in deriving Equation 38. h

c

a t t a c h e d to the a r o m a t i c a m i n o g r o u p , y i e l d s a f u n c t i o n of h i g h i n t r i n s i c a c t i v i t y . C o m p a r i s o n s of this t y p e d o n e e a r l y i n d r u g m o d i f i c a t i o n studies s h o u l d e n a b l e the d r u g designer to d e c i d e w h e t h e r or not he is p u r s u i n g a false l e a d . E q u a t i o n 42 is i n c l u d e d because it has a negative slope—i.e., this set of congeners w a s selected so that a l l m e m b e r s h a d a s u p e r o p t i m a l l i p o p h i l i c character.

E v i d e n c e n o w i n d i c a t e s (22,

25-27)

t h a t the g e n -

eral r e l a t i o n s h i p one s h o u l d expect b e t w e e n l o g 1 / C a n d l o g Ρ is p a r a b o l i c . T h e apex of the p a r a b o l a has b e e n t e r m e d l o g P . 0

Molecules having

this v a l u e of log Ρ h a v e i d e a l l i p o p h i l i c character for the system u n d e r c o n s i d e r a t i o n . S i n c e a l l of the a b o v e equations are l i n e a r i n l o g Ρ a d d i t i o n of a t e r m i n ( l o g P )

2

(the

does not i m p r o v e the c o r r e l a t i o n ) , greater

a c t i v i t y c o u l d h a v e b e e n o b t a i n e d i n each example b y d e s i g n i n g m o l e cules w i t h better l o g Ρ values. I n a l l examples except E q u a t i o n 42 this means i n c r e a s i n g the l i p o p h i l i c character.

E q u a t i o n 42 calls for

less

l i p o p h i l i c molecules. T h e r e are very f e w examples i n our d a t a b a n k w h e r e o n l y a n elec tronic term (σ, ρ Κ

α

or M . O . p a r a m e t e r s )

suffices to correlate structure

w i t h a c t i v i t y . T h i s accounts for the fact t h a t u p to this p o i n t m o l e c u l a r o r b i t a l c a l c u l a t i o n s (28, 29) of c h a r g e densities h a v e y i e l d e d so f e w e q u a tions c o r r e l a t i n g c h e m i c a l structure a n d b i o l o g i c a l a c t i v i t y i n q u a n t i t a t i v e terms.

H o w e v e r , the c o m b i n a t i o n of electron d i s t r i b u t i o n o b t a i n e d


via

34



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 h y d r o p h o b i c parameters does i n d i cate the v a l u e of s u c h c a l c u l a t i o n s (30, 31).

T o i l l u s t r a t e the c o m p a r a t i v e

v a l u e of the H a m m e t t σ constant, consider the f o l l o w i n g equations

cor

r e l a t i n g the 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 of p h o s p h a t e esters, V : ο II Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 19, 2016 | http://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch002

,0—Ρ—(OEt)

?

II I

H y d r o l y s i s (42 i n A q u e o u s S o l u t i o n , p H 7.6, 37°C) log k = 1.96 σ - -

6.62

in vitro I n h i b i t i o n F l y h e a d Cholinesterase -log I

5 0

in vivo L D

5 0

= 2.49 σ~ + 4.18

η 4

r 0.966

η

r

8

0.985

(42)

(43)

House Flies

η r -log I = 2.42

A Computerized Approach to Quantitative Biochemical

Recommend Documents