Molecular Orbital Studies of Biological Molecule Conformations

15 Molecular Orbital Studies of Biological

Downloaded by CALIFORNIA INST OF TECHNOLOGY on May 3, 2018 | https://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch015

Molecule Conformations L E M O N T B. KIER Massachusetts College of Pharmacy, 179 Longwood Ave., Boston, Mass. 02115

Over the past five years a number of studies have been reported on the prediction of biological molecule using molecular

orbital theory.

conformation

Several all-valence,

semi-

empirical molecular orbital methods have been used in these studies, with the extended Hückel theory (EHT)

being the

most widely used to date. The agreement between E H T -predicted conformations

of biological molecules and experi-

mental evidence has been quite significant.

A number of

hypotheses of drug mechanisms have been proposed, based on these calculations.

The utility of this approach and the

potential it affords for new insight into biological and mechanism research

warrant its incorporation

structure

into the

drug

armamentarium.

' T ' h e c o n f o r m a t i o n of a b i o l o g i c a l l y active m o l e c u l e v e r y l i k e l y p l a y s a n A

i m p o r t a n t p a r t i n the t o t a l s t r u c t u r a l characteristics c o n t r i b u t i n g to

a c t i v i t y . P r o n o u n c e d differences i n b i o l o g i c a l p o t e n c y i n a closely r e l a t e d c h e m i c a l series m a y w e l l be the result of m i n o r changes i n the p r e f e r r e d c o n f o r m a t i o n of these molecules. T h e result of these changes m a y be a n i n c o m p l e t e or a n i n a p p r o p r i a t e i n t e r a c t i o n w i t h a b i o l o g i c a l r e c e p t o r or e n z y m e . T h u s , some o p t i m u m p o s i t i o n i n g of essential features i n a n active m o l e c u l e m u s t b e necessary for b i o l o g i c a l efficacy. A k n o w l e d g e of c o n f o r m a t i o n a l preference is thus of v i t a l c o n c e r n . Evaluation

of

Conformation

T h e p r e d i c t i o n of the c o n f o r m a t i o n of m o l e c u l e s has b e e n of c o n s i d e r a b l e interest to b i o l o g i c a l scientists for m a n y years. E a r l y approaches 278

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

15.

KIER

Biological

Molecule

279

Conformations

centered o n a n i n t u i t i o n b a s e d o n the p r e s u m e d r e p u l s i v e i n t e r a c t i o n of b u l k y groups across space.

T h i s gave rise to g e n e r a l rules of c o n f o r m a -

t i o n a l preference w h i c h h a d s o m e u t i l i t y w i t h h y d r o c a r b o n s .

Unfortu-

n a t e l y , this i n t u i t i o n w a s u n a b l e to p e r c e i v e the a t t r a c t i v e forces w h i c h are also a p a r t of the t o t a l influence o n c o n f o r m a t i o n . A t t r a c t i v e forces are p a r t i c u l a r l y p r o m i n e n t i n h e t e r o a t o m molecules, a n d these are p r e d o m i n a n t l y w h a t the b i o l o g i c a l scientist encounters. Downloaded by CALIFORNIA INST OF TECHNOLOGY on May 3, 2018 | https://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch015

T h e a d v e n t of x - r a y c r y s t a l l o g r a p h y has p e r m i t t e d the m a p p i n g of the atoms of molecules i n the s o l i d state. T h e r e l e v a n c e of these conformations to s o l u t i o n p h e n o m e n a is, h o w e v e r , obscure. I n the c r y s t a l , t h e m o l e c u l e s are closely p a c k e d , i n t e r a c t i n g w i t h e a c h other a n d w i t h gegenions i f present. T h i s is p r o b a b l y not the situation n o r m a l l y e n c o u n t e r e d i n the d i l u t e solutions of the b i o l o g i c a l m i l i e u x . T h u s , b i o l o g i c a l conclusions d e rived from x-ray-derived conformations must always be considered i n this l i g h t . A m o r e u s e f u l e x p e r i m e n t a l a p p r o a c h to p r e d i c t i n g c o n f o r m a t i o n i n a b i o l o g i c a l e n v i r o n m e n t is t h r o u g h the use of N M R analysis i n w a t e r . T h e s e d a t a , i f p r o p e r l y a n a l y z e d , g i v e a t i m e average c o n f o r m a t i o n w h i c h c a n be of c o n s i d e r a b l e v a l u e i n subsequent b i o l o g i c a l i n t e r p r e t a t i o n s . It is necessary, h o w e v e r , a c t u a l l y to have the c o m p o u n d u n d e r study, a n d f r e q u e n t l y the analysis of the N M R d a t a is e x t r e m e l y c o m p l e x . O t h e r s o l u t i o n t e c h n i q u e s for p r e d i c t i n g p r e f e r r e d c o n f o r m a t i o n i n c l u d e O R D , d i p o l e m o m e n t a n d spectroscopic m e t h o d s . E a c h is c a p a b l e of g i v i n g u s e f u l p a r t i a l i n f o r m a t i o n o n m o l e c u l a r c o n f o r m a t i o n . E a c h , of course, requires that the c o m p o u n d be a c t u a l l y a v a i l a b l e for study. Molecular

Orbital Prediction

of

Conformation >

A n o t h e r a p p r o a c h w h i c h has b e c o m e a v a i l a b l e i n the past d e c a d e is the use of a l l - v a l e n c e e l e c t r o n , s e m i e m p i r i c a l m o l e c u l a r o r b i t a l t h e o r y . T h i s a p p r o x i m a t i o n of q u a n t u m m e c h a n i c s makes it possible to c a l c u l a t e for f a i r l y large m o l e c u l e s , a t o t a l energy b e h a v i n g i n a n a p p r o x i m a t e l y p a r a l l e l f a s h i o n to the t r u e m o l e c u l a r energy.

T h e c o n s i d e r a t i o n of a l l

v a l e n c e electrons makes this c a l c u l a t e d t o t a l energy sensitive to the c o n f o r m a t i o n of the m o l e c u l e . T h u s , energy m i n i m i z a t i o n as a f u n c t i o n of b o n d angle v a r i a t i o n is possible, a n d the p r e d i c t i o n of a p r e f e r r e d c o n f o r m a t i o n is a consequence. T h e first of these m e t h o d s was d e v e l o p e d b y H o f f m a n n i n 1963 ( 1 ) a n d is k n o w n as extended H i i c k e l t h e o r y ( E H T ) .

B r i e f l y , the m e t h o d

uses H i i c k e l f o r m a l i s m ; h o w e v e r , e x p l i c i t c o n s i d e r a t i o n of

non-bonded

interactions a n d a l l o v e r l a p integrals are a refinement. Slater o r b i t a l s are u s e d , a n d the c o m p u t a t i o n s r e q u i r e o n l y one p a r a m e t e r , the v a l e n c e state i o n i z a t i o n p o t e n t i a l for the C o u l o m b i n t e g r a l a n d i n d i r e c t l y f o r the reso-



280

BIOLOGICAL CORRELATIONS

T H E HANSCH

APPROACH

Figure 1. Predicted conformation of acetylcholine in "muscarinic" variant n a n c e i n t e g r a l . T h e t h e o r y , merits, a n d evaluations of E H T h a v e reported

been

(2-4).

M o r e r e c e n t l y , a n a l l v a l e n c e electron, s e m i e m p i r i c a l m o l e c u l a r o r b i t a l t h e o r y k n o w n as the C o m p l e t e N e g l e c t of D i f f e r e n t i a l O v e r l a p ( C N D O ) has b e e n p r o p o s e d b y P o p l e b a s e d o n self-consistent field ( S C F ) f o r m a l ism (5).

A l t h o u g h this m e t h o d uses a m o r e s o p h i s t i c a t e d a p p r o x i m a t i o n

of the w a v e f u n c t i o n , i t neglects differential o v e r l a p . C o m p a r i s o n s of these t w o methods r e v e a l t h e i r r e l a t i v e strengths a n d shortcomings (4).

I n g e n e r a l , the C N D O m e t h o d is s u p e r i o r f o r charges,

E H T p r e d i c t i n g greatly exaggerated values.

T h e m a j o r v a l u e of E H T

lies i n its a b i l i t y to p r e d i c t c o r r e c t l y t h e p r e f e r r e d c o n f o r m a t i o n . T h i s has b e e n d e m o n s t r a t e d for n u m e r o u s h y d r o c a r b o n s for a v a r i e t y of h e t e r o a t o m molecules

(1)

and more

recently

(6,7).

A l a r g e n u m b e r of m o l e c u l a r o r b i t a l p r e d i c t i o n s of b i o l o g i c a l m o l e c u l e conformations h a v e b e e n a c c o m p l i s h e d u s i n g E H T . T h e r e c o r d of agreement 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 values has b e e n excellent. A significant a m o u n t of u s e f u l i n f o r m a t i o n has e m e r g e d f r o m these p r e d i c t i o n s p e r t i n e n t to 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 s , the c o n s i d e r a t i o n of m o l e c u l a r m e c h a n i s m s , a n d the r a t i o n a l e for n e w d r u g d e s i g n

(7).

W e a t t e m p t to s u m m a r i z e M O c o n f o r m a t i o n studies t h r o u g h A p r i l 1972


15.

KiER

Biological

Molecule

281

Conformations

a n d at the same t i m e to assess the v a l i d i t y of

these p r e d i c t i o n s i n

the l i g h t of e x p e r i m e n t a l e v i d e n c e a n d b i o l o g i c a l k n o w l e d g e . Muscarinic

Agents

T h e first a p p l i c a t i o n of a l l - v a l e n c e electron M O theory to p r e d i c t the c o n f o r m a t i o n of a n e u r o t r a n s m i t t e r was r e p o r t e d i n 1967 o n a c e t y l -


c h o l i n e ( 8 ). U s i n g E H T , the c o n f o r m a t i o n of a c e t y l c h o l i n e was p r e d i c t e d to assume a n a p p r o x i m a t e l y g a u c h e r e l a t i o n s h i p b e t w e e n the n i t r o g e n a n d ether o x y g e n atoms. T h i s is i n agreement w i t h e x p e r i m e n t a l e v i d e n c e d e r i v e d f r o m aqueous s o l u t i o n N M R studies ( 9 ) .

Some

flexibility

was

p r e d i c t e d for the C O - O b o n d so that the d i m e n s i o n s b e t w e e n the heteroatoms w e r e p r e d i c t e d as s h o w n i n F i g u r e 1. I n the same s t u d y E H T p r e d i c t i o n s w e r e r e p o r t e d for the potent m u s c a r i n i c agents m u s c a r i n e , F i g u r e 2, a n d m u s c a r o n e , F i g u r e 3 ( 8 ) .

The

e x p e r i m e n t a l evidence a v a i l a b l e for c o m p a r i s o n are x-ray analyses of t h e m u s c a r i n e (10)

a n d m u s c a r o n e (80)

crystals, w i t h w h i c h the p r e d i c t e d

conformations agree. S u p e r p o s i t i o n i n g these three potent m u s c a r i n i c agents, i n their p r e f e r r e d conformations r e s u l t e d i n the o b s e r v a t i o n of a c o m m o n p a t t e r n of s i m i l a r l y c h a r g e d s t r u c t u r a l features. T h e p a t t e r n , F i g u r e 4, was p r o p o s e d as the m u s c a r i n i c p h a r m a c o p h o r e (8).

T h i s p a t t e r n , p r e d i c t e d f r o m theo-

r e t i c a l considerations, bears a s t r i k i n g s i m i l a r i t y to the m u s c a r i n i c p h a r m a c o p h o r e p r o p o s e d b y B e c k e t t b a s e d o n extensive s t r u c t u r e - a c t i v i t y studies

Figure 2.

Predicted conformation muscarine

of



282


Figure

(11).

Predicted conformation muscarone

of

R e c e n t M O c a l c u l a t i o n s o n these molecules u s i n g a m o d i f i e d C N D O

method

(12)

and

an

( I N D O ) m e t h o d (13) and

3.

T H E HANSCH APPROACH

intermediate

Neglect

of

Differential Overlap

are i n g e n e r a l agreement w i t h E H T p r e d i c t i o n s

e x p e r i m e n t a l evidence.

A s t u d y of the potent m u s c a r i n i c

agent,

S ( + ) - a c e t y l - / ^ m e t h y l c h o l i n e u s i n g b o t h N M R a n d m o l e c u l a r r o t a t i o n to p r e d i c t the s o l u t i o n c o n f o r m a t i o n , r e v e a l e d that this m o l e c u l e the p a t t e r n p r e d i c t e d i n F i g u r e 4 (14), of these p r e d i c t i o n s .

Figure 4.

assumes

thus l e n d i n g s u p p o r t to the v a l i d i t y

Proposed muscarinic cophore

pharma-


15.

Biological

KIER

Molecule

283

Conformations

C a l c u l a t i o n s o n o x o t r e m o r i n e (15),

p r e s u m e d to be a C N S m u s c a r i n i c

agent, r e v e a l e d that this m o l e c u l e , i n its p r e d i c t e d c o n f o r m a t i o n ( F i g u r e 5) m i m i c k s this p r e d i c t e d m u s c a r i n i c p h a r m a c o p h o r e .

T h e assumption

is m a d e that the e l e c t r o n i c c h a r a c t e r of the t r i p l e b o n d is the receptor e q u i v a l e n t of the ether o x y g e n a t o m i n a c e t y l c h o l i n e as p r o p o s e d B e b b i n g t o n (16).

by

T h e s e c a l c u l a t i o n s s u p p o r t his p r o p o s a l a n d r e v e a l

h o w oxotremorine m a y m e e t the s t r u c t u r a l r e q u i r e m e n t s of a m u s c a r i n i c


agent.

Figure 5. Nicotinic

Predicted conformation

of

oxotremonne

Agents

T h e p r e d i c t i o n of the p r e f e r r e d c o n f o r m a t i o n of the n i c o t i n i c m o n o c a t i o n was r e p o r t e d i n 1968 (17).

T w o c o n f o r m a t i o n s w e r e p r e d i c t e d to

coexist ( F i g u r e 6 ) i n agreement w i t h N M R studies (18). m o d i f i e d C N D O calculations are i n agreement (12).

Subsequent

O n e of these n i c o t i n e

conformers, F i g u r e 6 ( t o p ) , presented a n i n t e r n i t r o g e n distance close to the o n i u m g r o u p - c a r b o n y l o x y g e n distance p r e v i o u s l y p r e d i c t e d for acet y l c h o l i n e . It is necessary, i n this c o m p a r i s o n , to i n v o k e a p r e d i c t e d c o n f o r m a t i o n of a c e t y l c h o l i n e i n w h i c h the flexible c a r b o n y l g r o u p is r o t a t e d 60° as s h o w n i n F i g u r e 7. It w a s p r e d i c t e d that F i g u r e 6 ( t o p ) is the act i v e c o n f o r m e r of n i c o t i n e a n d that F i g u r e 7 is the n i c o t i n i c c o n f o r m a t i o n of a c e t y l c h o l i n e .

T h e n i c o t i n i c p h a r m a c o p h o r e w a s p r o p o s e d to b e as

s h o w n i n F i g u r e 8. A s a result of these t w o studies (8, 17),

it was p r o p o s e d that a c e t y l -

c h o l i n e exhibits t w o different p h a r m a c o l o g i c a l actions b y v i r t u e of its b e i n g c a p a b l e of p r e s e n t i n g to the receptors, t w o different groups of atoms i n the a c e t y l c h o l i n e m o l e c u l e i n t w o different c o n f o r m a t i o n s of the c a r bonyl group. A n E H T c a l c u l a t i o n o n the potent n i c o t i n i c agent p h e n y l c h o l i n e ether s h o w e d t h a t this m o l e c u l e prefers a g a u c h e c o n f o r m a t i o n of the hetero-



284

BIOLOGICAL

Figure 6.

CORRELATIONS

Predicted nicotine

T H E HANSCH

APPROACH

conformations

Figure 7. Predicted conformation of acetylcholine in "nicotinic" variant


15.

Biological

KIER

Molecule

0 8 4.85

X

285

Conformations

± 0.1

I Θ Ν—

A

Figure 8. Proposed nicotinic pharmacophore


atoms, F i g u r e 9 ( 1 9 ) .

T h e p h e n y l r i n g w a s f o u n d to p r e f e r a c o n f o r m a t i o n

r e l a t i v e to the side c h a i n so t h a t a n ortho p o s i t i o n is a b o u t 4.7 A f r o m the o n i u m n i t r o g e n . T h i s p r e d i c t i o n of a g a u c h e side c h a i n c o n f o r m a t i o n i n p h e n y l c h o l i n e ether is i n agreement f o u n d for x y l o c h o l i n e (20).

w i t h the c r y s t a l c o n f o r m a t i o n

P r e v i o u s studies h a v e s h o w n a c o r r e l a t i o n

b e t w e e n the f r o n t i e r electron d e n s i t y (21) (22)

a n d the e l e c t r o p h i l i c r e a c t i v i t y

of this p o s i t i o n a n d n i c o t i n i c a c t i v i t y . T h e c o n f o r m a t i o n a l p r e d i c

t i o n of the m o l e c u l e thus reveals that the ortho p o s i t i o n is b o t h s p a t i a l l y a n d e l e c t r o n i c a l l y c a p a b l e of f u l f i l l i n g the s t r u c t u r a l r e q u i r e m e n t s

for

n i c o t i n i c a c t i v i t y as p r e v i o u s l y p r o p o s e d ( F i g u r e 8 ) . R e c e n t E H T c a l c u l a t i o n s o n the neostigmine m o l e c u l e h a v e l e d to a c o n f o r m a t i o n p r e d i c t i o n l o c a t i n g the o n i u m g r o u p a b o u t 4.5 A f r o m the carbonyl oxygen cophore

(81)

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

(17).

Cholinesterase

Inhibitor

T h e first a p p l i c a t i o n of a l l - v a l e n c e M O theory to a p h a r m a c o l o g i c a l l y active agent was the E H T s t u d y of the cholinesterase i n h i b i t o r 2 - f o r m y l N - m e t h y l p y r i d i n i u m oxime

(2-PAM ) +

(23).

T h e aldoxime group

f o u n d to prefer a c o n f o r m a t i o n p e r p e n d i c u l a r to the r i n g p l a n e .

was Crys-

t a l l o g r a p h i c d a t a i n d i c a t e that the a l d o x i m e g r o u p is c o p l a n e r w i t h t h e r i n g i n the s o l i d state (24).

T h e c r y s t a l is y e l l o w w h i l e a n a c i d s o l u t i o n

is colorless, l e n d i n g s u p p o r t to the b e l i e f that the M O c a l c u l a t i o n s cor rectly predict a non-conjugated

f o r m a n d that calculations of this k i n d

are r e l e v a n t to d i l u t e s o l u t i o n p h e n o m e n a b u t not necessarily to c r y s t a l structure

(20).

Histamine M o l e c u l a r o r b i t a l calculations l e d to the p r e d i c t i o n that t w o d i s t i n c t l y different conformations of e q u a l preference p r e v a i l e d for h i s t a m i n e ( F i g ure 10) (25).

T h e c o n f o r m a t i o n of F i g u r e 10 ( b o t t o m ) w a s p r e d i c t e d to

exist w i t h o u t a n y h y d r o g e n b o n d i n g b e t w e e n a n o n i u m h y d r o g e n a n d the r i n g n i t r o g e n a t o m . R e c e n t N M R analysis of a n aqueous s o l u t i o n of h i s t a m i n e r e v e a l e d that the t w o conformers p r e d i c t e d f r o m E H T - M O d o i n fact


286

CORRELATIONS

T H E HANSCH

APPROACH


BIOLOGICAL

Figure 10.

Predicted histamine

conformations


15.

KiER

Biological

Molecule

exist i n e q u a l p r o p o r t i o n s {26).

287

Conformations

F u r t h e r m o r e , the p r e d i c t i o n of no i n t r a

m o l e c u l a r h y d r o g e n b o n d i n g i n aqueous s o l u t i o n has also b e e n c o n f i r m e d e x p e r i m e n t a l l y (27).

A recent m o d i f i e d C N D O c a l c u l a t i o n o n h i s t a m i n e

p r e d i c t s o n l y a single m o d i f i e d g a u c h e c o n f o r m a t i o n to p r e d o m i n a t e

(28).

O n t h e basis of the p r e d i c t i o n of t w o coexisting conformers of h i s t a m i n e , the hypothesis w a s p r o p o s e d that one c o n f o r m e r w a s responsible for the H i - r e c e p t o r a c t i v i t y a n d the other for H - r e c e p t o r a c t i v i t y (25).

The

2


top c o n f o r m e r i n F i g u r e 10 w a s p r o p o s e d as the H i - r e c e p t o r agonist o n the basis of a n i n t e r n i t r o g e n distance c o m p a r a b l e w i t h the p r e s u m e d i n t e r n i t r o g e n distance i n the a n t i h i s t a m i n i c t r i p r o l i d i n e . T h e b o t t o m c o n f o r m e r i n F i g u r e 10 was thus p r o p o s e d as b e i n g the agonist for H - r e 2

ceptor a c t i v i t y . T h i s latter p r e d i c t i o n thus p r o v i d e s a r a t i o n a l e for the synthesis of p o t e n t i a l a c i d antisecretory agents.

Figure 11.

Predicted serotonin

conformation

Serotonin T h e p r e f e r r e d c o n f o r m a t i o n of serotonin ( 5 - h y d r o x y t r y p t a m i n e ) was p r e d i c t e d u s i n g E H T - M O ( F i g u r e 11) ( 2 9 ) .

A modified C N D O calcu

l a t i o n p r e d i c t s a p r e f e r r e d c o n f o r m a t i o n i n w h i c h the C—Ν b o n d n e a r l y eclipses the r i n g - C b o n d w i t h the o n i u m g r o u p l y i n g over the b e n z e n e r i n g (30).

A n I N D O c a l c u l a t i o n p r e d i c t s a strong preference for a c o n

f o r m a t i o n i n w h i c h the C - N b o n d eclipses the r i n g - C b o n d a n d the o n i u m


288


g r o u p lies over the i n d o l e 2 p o s i t i o n ( 3 1 ) . m o l e c u l e (82) (29)

T H E HANSCH APPROACH

A recent N M R analysis of the

reports a trans preference, i n s u p p o r t of the E H T s t u d y

a n d i n contrast to the p r e d i c t i o n s b y other methods. T h e E H T p r e -

d i c t e d distance b e t w e e n the t w o n i t r o g e n atoms is v e r y close to the i n t e r n i t r o g e n distance f o u n d i n the c o m p e t i t i v e i n h i b i t o r l y s e r g i c a c i d d i e t h y l a m i d e ( L S D ) . It is reasonable to p r e s u m e that a c o m p e t i t i v e i n h i b i t o r m u s t p a r t i a l l y m i m i c the p h a r m a c o p h o r e

of the agonist; h e n c e

these


s i m i l a r distances are consistent w i t h the p r e d i c t e d c o n f o r m a t i o n .

Figure 12.

Predicted side chain conformations steroids

of 17-keto

It is i n t e r e s t i n g to c o n t e m p l a t e the s t r u c t u r a l s i m i l a r i t y p r e d i c t e d f o r L S D a n d serotonin a n d the k n o w n C N S a c t i v i t y of the f o r m e r a n d to c o m p a r e this w i t h the C N S a c t i v i t y a n d structure of the c a n n i b i n o l m e t a b o l i t e , l l - h y d r o x y - A - t e t r a h y d r o c a n n a b i n o l . It is c o n c e i v a b l e 9

that

s i m i l a r m e c h a n i s m s m a y p r e v a i l i n the C N S as a result of s i m i l a r stereoc h e m i c a l presentations of c o m p a r a b l e c h a r g e d atoms to the serotonin receptor.


15.

KiER

Pregnane

Biological

Molecule

289

Conformations

Steroids

T h e side c h a i n conformations of progesterone,

corticosterone,

Cortisol w e r e p r e d i c t e d u s i n g E H T - M O ( F i g u r e 12) (32).

and

A l l three side

chains w e r e p r e d i c t e d to f o r m a p l a n e w i t h the 17«-substituent. T h e p r e d i c t i o n of the progesterone side c h a i n c o n f o r m a t i o n is w i t h i n 30° of a s o l u t i o n d i p o l e m o m e n t s t u d y (33).

T h e p r e d i c t i o n s of the corticosterone


a n d Cortisol conformations are i n close a g r e e m e n t w i t h e x p e r i m e n t a l r e sults f r o m i n f r a r e d a n d N M R studies (34, 35).

A reflection of t h e β - f a c e

of Cortisol, i n its p r e d i c t e d c o n f o r m a t i o n , is s h o w n i n F i g u r e 13.

ΘΝ

C

Figure

13.

Predicted β-face Cortisol

3

pattern

of

P o r t i o n s of the p r e d i c t e d Cortisol p a t t e r n of c h a r g e d atoms ( F i g u r e 13) w e r e o b s e r v e d to be c o m p a r a b l e w i t h c h a r g e d patterns for either h i s t a m i n e (25)

or serotonin (29).

Since these t w o amines h a v e b e e n i m

p l i c a t e d as b e i n g i n f l a m m a g e n i c (36) m a t o r y agent (37),

a n d Cortisol is a potent a n t i - i n f l a m

i t was p o s t u l a t e d that Cortisol m i g h t evoke this a c t i o n

b y a n i n t e r a c t i o n w i t h either or b o t h h i s t a m i n e a n d serotonin receptors b y v i r t u r e of these c o m m o n s t r u c t u r a l features. T h e hypothesis has r e c e i v e d some e x p e r i m e n t a l s u p p o r t f r o m the recent o b s e r v a t i o n that Cortisol is effective i n c o m p e t i n g for h i s t a m i n e b i n d i n g sites o n b i o p o l y m e r s (38).

A subsequent E H T - M O s t u d y i n v o l v -


290


T H E HANSCH

APPROACH

i n g n o n - s t e r o i d a l a n t i - i n f l a m m a t o r y agents i n c l u d i n g i n d o m e t h a c i n c o n firmed

that the c o m m o n s t r u c t u r a l patterns p r e d i c t e d p r e v a i l e d i n these

drugs ( 3 9 ) .

T h e p r e d i c t e d c o n f o r m a t i o n of i n d o m e t h a c i n is i n agreement

w i t h the r e p o r t e d c r y s t a l structure of this m o l e c u l e (83).

It is i n t e r e s t i n g

to c o n t e m p l a t e the roles of serotonin as a platelet aggregation p r o m o t e r a n d the c o m m o n a n t i - i n f l a m m a t o r y agents as platelet a g g r e g a t i o n i n h i b i


tors as a possible p a r a l l e l to this hypothesis of a n t i - i n f l a m m a t o r y a c t i v i t y . Adrenergic

Agents

E H T - M O p r e d i c t i o n s of e p h e d r i n e a n d p s e u d o - e p h e d r i n e h a v e b e e n r e p o r t e d ( F i g u r e 14) (2)

(35).

T h e c o n f o r m a t i o n p r e d i c t e d for e p h e d r i n e

is i n agreement w i t h N M R analysis (41, 42);

h o w e v e r , the p r e d i c t i o n

of the p s e u d o - e p h e d r i n e c o n f o r m a t i o n agrees o n l y w i t h a m i n o r c o n t r i b u t o r to the s o l u t i o n e q u i l i b r i u m (42).

T h e p r e d i c t e d c o n f o r m a t i o n for

the α-adrenergic agonist, n o r e p i n e p h r i n e , prese^ s the same p h a r m a c o p h o r e (43). (44).

T h i s p r e d i c t i o n is i n agreement w i t h the c r y s t a l c o n f o r m a t i o n

O t h e r studies u s i n g the I N D O

(45)

and C N D O

(84)

methods

p r e d i c t a trans a n d a g a u c h e c o n f o r m a t i o n to coexist.

Figure

14.

Predicted conformations and pseudoephedrine

of

ephedrine

It is w e l l k n o w n that a n u n s u b s t i t u t e d c a t e c h o l a m i n e s u c h as n o r e p i n e p h r i n e or a m o n o m e t h y l d e r i v a t i v e l i k e e p i n e p h r i n e or e p h e d r i n e is p r e d o m i n a n t l y α-adrenergic. I n c r e a s i n g the b u l k of the m o n o a l k y l s u b -


15.

KiER

Biological

Molecule

291

Conformations

stituent i n this series increases ^ - a d r e n e r g i c a c t i v i t y w h i l e at the same t i m e α-adrenergic a c t i v i t y is o b l i t e r a t e d . T h u s , i s o p r o p y l n o r e p i n e p h r i n e ( i s o p r o t e r a n o l ) is a s t a n d a r d for almost p u r e ^ - a d r e n e r g i c a c t i v i t y . T w o theories h a v e b e e n p r o p o s e d to e x p l a i n this r e v e r s i n g p a i r of trends i n the c a t e c h o l a m i n e series. O n e t h e o r y proposes that the i n c r e a s i n g b u l k of the N - s u b s t i t u e n t increases the b a r r i e r to r o t a t i o n b e t w e e n the m e t h y l e n e groups so that the ease of a s s u m i n g a gauche Downloaded by CALIFORNIA INST OF TECHNOLOGY on May 3, 2018 | https://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch015

w i l l b e a f u n c t i o n of the N - s u b s t i t u e n t b u l k (46).

conformation

T h e theory t h e n p r o

poses t h a t the different conformers, gauche a n d trans, cause t w o different reactions to occur, e a c h c h a r a c t e r i s t i c of the a- or β-adrenergic receptor. T h e second t h e o r y proposes that the N - s u b s t i t u e n t influences the c h a r g e o n the o n i u m g r o u p w h i c h influences the r e a c t i v i t y to one or the other a d r e n e r g i c receptor

(47).

A recent s t u d y u s i n g E H T for c o n f o r m a t i o n a n d C N D O a n d ab

initio

calculations for c h a r g e densities has b e e n r e p o r t e d o n the c a t e c h o l a m i n e series n o r e p i n e p h r i n e , e p i n e p h r i n e , N - e t h y l n o r e p i n e p h r i n e , a n d i s o p r o t e r a n o l (48).

T h e s e studies r e v e a l e d no p r e d i c t e d c h a n g e i n the trans

preference for a n y of the series. F u r t h e r , t h e y s h o w e d a n almost i d e n t i c a l energy of the b a r r i e r f r o m a trans to a gauche c o n f o r m a t i o n for a l l m e m bers of the series. T h e s e results argue against the t h e o r y of v a r i a b l e flexi b i l i t y of the m e t h y l e n e - m e t h y l e n e b o n d

(46).

C h a r g e densities w e r e

c a l c u l a t e d o n s i m u l a t e d o n i u m systems u s i n g b o t h C N D O a n d ab m e t h o d s (48).

initio

T h e s e results r e v e a l e d no a p p r e c i a b l e c h a n g e i n o n i u m

charge i n the series, w h i c h is at v a r i a n c e w i t h the charge t h e o r y

(47).

A n alternate t h e o r y was p r o p o s e d , b a s e d o n these c a l c u l a t i o n s .

It

was p o s t u l a t e d that α-adrenergic a c t i v i t y r e q u i r e s a n o n i u m h y d r o g e n a t o m , p r o b a b l y as a h y d r o g e n b o n d donor.

T h e ^ - a d r e n e r g i c receptor,

h o w e v e r , w a s p o s t u l a t e d to r e q u i r e a n a l k y l g r o u p at the N - s u b s t i t u e n t p o s i t i o n . It was p r o p o s e d that this N - s u b s t i t u e n t was i n v o l v e d i n a d i s p e r s i o n i n t e r a c t i o n w i t h the r e c e p t o r a n d was o p t i m a l w h e n there w a s a b r a n c h e d h y d r o c a r b o n s u c h as a n i s o p r o p y l g r o u p . T h e s e authors r a i s e d the i n t r i g u i n g suggestion that the o n i u m g r o u p w a s p e r h a p s not essential for ^ - a d r e n e r g i c a c t i v i t y a n d that a m e t h y l e n e g r o u p c o u l d r e p l a c e i t . It was n o t e d that s u c h a c o m p o u n d h a d r e c e n t l y b e e n m a d e a n d r e p o r t e d (49).

T h i s c o m p o u n d , the m e t h y l e n e a n a l o g of i s o p r o t e r a n o l was f o u n d

to h a v e modest ^ - a d r e n e r g i c a c t i v i t y (49).

A p a r a l l e l was also d r a w n

b e t w e e n this hypothesis a n d the structure a n d ^ - a d r e n e r g i c a c t i v i t y of prostaglandin E i

(48).

Dopamine A n E H T c a l c u l a t i o n o n d o p a m i n e , c o n s i d e r i n g the p h e n y l - m e t h y l e n e a n d m e t h y l e n e - m e t h y l e n e b o n d s a n d h o l d i n g the h y d r o x y l s out of the


292


T H E HANSCH

APPROACH

Θ H N 3

i

θ

I


θ

>

Ν

0 Π Figure 15. Predicted conforma tion of gamma-aminobutyric acid r i n g p l a n e l e d to a gauche p r e d i c t i o n for the side c h a i n ( 5 0 ) . E H T c a l c u l a t i o n , a p p a r e n t l y c o n s i d e r i n g o n l y the b o n d , r e p o r t e d a trans p r e f e r e n c e (85).

Another

methylene-methylene

A C N D O - t y p e c a l c u l a t i o n has

r e p o r t e d a trans a n d g a u c h e preference (84).

R e c a l c u l a t i o n of t h e m o l e

c u l e h o l d i n g the h y d r o x y l s i n the r i n g p l a n e leads to a trans side c h a i n conformation

(77).

C r y s t a l analysis p r e d i c t s

p r e d i c t s b o t h trans a n d g a u c h e γ-Aminobutyric

(86)

while

NMR

Acid

T h e p r e f e r r e d conformations aminobutyric acid c a l c u l a t e d (51).

trans

(85).

(GABA)

of the i n h i b i t o r y transmitter

gamma-

a n d a G A B A - l i k e agent, m u s c i m o l ,

T h e p r e d i c t e d conformations

were

( F i g u r e 15) r e v e a l a close

c o r r e s p o n d e n c e b e t w e e n the o n i u m g r o u p a n d c h a r g e d o x y g e n distance i n the t w o molecules.

It has r e c e n t l y b e e n r e p o r t e d that b i c u c u l l i n e is a

specific i n h i b i t o r of G A B A

(52).

E x a m i n a t i o n of D r e i d i n g m o d e l s

b i c u c u l l i n e or the free a c i d r e v e a l that this m o l e c u l e , as a

of

protonated

salt, c a n assume a reasonable c o n f o r m a t i o n i n w h i c h the o n i u m to o x y g e n distance is c o m p a r a b l e

w i t h the p r e d i c t i o n for G A B A

R e c e n t c a l c u l a t i o n s c o n f i r m this i n t e r a t o m i c distance

and

muscimol.

(77).

Τ hyrontimetics T r i s u b s t i t u t e d t h y r o n i n e analogs h a v e b e e n s t u d i e d u s i n g E H T to p r e d i c t the p h e n o x y p h e n y l c o n f o r m a t i o n stituents ( F i g u r e 16) ( 5 3 ) .

as i n f l u e n c e d b y the 3,5-sub-

E H T p r e d i c t i o n s i n d i c a t e d that 3,5-iodo a n d

3,5-bromo g r o u p s i n f l u e n c e d a p r e f e r e n c e as s h o w n i n F i g u r e 16, i n agree-


15.

KIER

Biological

Molecule

m e n t w i t h c r y s t a l studies (54, 87).

293

Conformations

R e c e n t reports that a n iodine-free b r o -

m o t h y r o n i n e is t h y r o m i m e t i c suggest that the roles of these t w o halogens m i g h t b e to c o n t a i n the t w o rings as s h o w n i n F i g u r e 16 ( 5 5 ) .

The M O

c a l c u l a t i o n s f u r t h e r p r e d i c t e d t h a t 3,5-chloro o r h y d r o g e n analogs p r e f e r r e d alternate conformations to that s h o w n i n F i g u r e 16, i n w h i c h the t w o r i n g planes intersect l i k e pages i n a book. T h e k n o w l e d g e t h a t the c h l o r i n e or h y d r o g e n analogs are i n a c t i v e suggests a p r e d o m i n a n t l y steric Downloaded by CALIFORNIA INST OF TECHNOLOGY on May 3, 2018 | https://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch015

role f o r these atoms. Amino Acids and Peptides A l l valence electron M O calculations have been extended p r e d i c t i o n of a m i n o a c i d r e s i d u e conformations.

to

the

T h e a p p r o a c h has g e n

e r a l l y b e e n to consider a m o d e l c o m p o u n d , s u c h as a n N - a c y l a m i n o a c i d a m i d e to s i m u l a t e the m i d - c h a i n residue. B e g i n n i n g w i t h three i n d e p e n d ent studies r e p o r t e d i n 1969 ( 56—58) a. n u m b e r of a m i n o a c i d r e s i d u e c o n f o r m a t i o n s have b e e n p r e d i c t e d to date f r o m a l l v a l e n c e M O m e t h o d s . Specific examples of a m i n o a c i d residues s t u d i e d , w i t h references i n o r d e r of a p p e a r a n c e i n the l i t e r a t u r e are g l y c i n e (56-^59), a l a n i n e (56, 57,

59),

p h e n y l a l a n i n e (57),

(61,

p r o l i n e (57,

62), i s o l e u c i n e (61, 88),

60),

v a l i n e (61,88),

a r g i n i n e ( N - t e r m i n a l ) (63),

h y d r o x y p r o l i n e (60), t h r e o n i n e (62),

serine

leucine

a r g i n i n e ( C - t e r m i n a l ) (63),

(61,88),

a r g i n i n e side

θ

α.

HO,

Figure 16. Predicted conformation of 3,5,3 -triiodo or tribromothyronine f



294


Figure 17. c h a i n (63, 64),

Predicted conformation

of insect juvenile

APPROACH

hormone

a r g i n i n e a n d lysine residues ( 6 5 ) , N - t e r m i n a l g l y c i n e , a l a

n i n e , a n d p r o l i n e (66, 89), o n i n e (90),

T H E HANSCH

aspartic a c i d (88),

and tryptophan

g l u t a m i c a c i d (88),

methi

(90).

I n g e n e r a l t h e p r e d i c t e d conformations h a v e a g r e e d w i t h some ex p e r i m e n t a l results o b t a i n e d f r o m v a r i o u s p o l y p e p t i d e s

u s i n g different

e x p e r i m e n t a l techniques. T h e existence of m o r e t h a n one f o r m of a p o l y p e p t i d e r e s u l t i n g f r o m different conformations possible for some a m i n o a c i d residues, d e p e n d i n g o n p h y s i c a l a n d c h e m i c a l m a n i p u l a t i o n s , makes v a l i d a t i o n of these p r e d i c t i o n s complex. T w o attempts h a v e b e e n r e p o r t e d to p r e d i c t t h e c o n f o r m a t i o n of a polypeptide hormone

b y a s s e m b l i n g the a p p r o p r i a t e residues i n t h e i r

p r e d i c t e d c o n f o r m a t i o n (63,90).

I n this m a n n e r , t h e a m i n o a c i d sequence

of b r a d y k i n i n w a s p r e d i c t e d to exist i n a r a n d o m c o i l c o n f o r m a t i o n , w i t h v a r i a t i o n a r o u n d the g l y c i n e φ b o n d , a n d w i t h no i n t e r a c t i o n p r e d i c t e d b e t w e e n p h e n y l groups. prediction; however,

A s yet no e x p e r i m e n t a l e v i d e n c e confirms this

existing e x p e r i m e n t a l e v i d e n c e

p r e d i c t i o n is reasonable (67-69).

of g a s t r i n t e t r a p e p t i d e w a s p r e d i c t e d Other Biologically

suggests

t h a t the

I n the second s t u d y the c o n f o r m a t i o n (90).

Important Molecules

A n u m b e r of other studies have b e e n r e p o r t e d , u s i n g a l l - v a l e n c e M O m e t h o d s to p r e d i c t the c o n f o r m a t i o n of b i o l o g i c a l l y i m p o r t a n t m o l e c u l e s . These include calculations on glucopyranose (71),

several nucleosides (72-75),

(70),

several d i s a c c h a r i d e s

a n d a c e t a n i l i d e (76).

The prediction

of the c o n f o r m a t i o n of the insect j u v e n i l e h o r m o n e has also b e e n f r o m E H T - M O c a l c u l a t i o n s ( F i g u r e 17)

(77).

made

U s i n g a c o m b i n a t i o n of


15.

KIER

Biological

Molecule

Conformations

295

E H T , iterative E H T , a n d dispersion b o n d i n g calculations, the conforma tions o f p r o s t a g l a n d i n E - l w e r e p r e d i c t e d

(78).

T h e prominent con-

formers w e r e a l l p r e d i c t e d t o h a v e i n t i m a t e i n t e r a c t i o n b e t w e e n t h e side chains, i n agreement w i t h c r y s t a l studies ( 7 9 ) . F i n a l l y , p r e d i c t i o n s o f c o n f o r m a t i o n h a v e l e d to t h e p r e d i c t i o n of a sweet-taste

pharmacophore

(91).


Perspectives T h e relevance o f t h e p r e f e r r e d c o n f o r m a t i o n o f a n active m o l e c u l e to events a t its b i o l o g i c a l r e c e p t o r is u n c e r t a i n . T h e finding i n several studies, t h a t s t r u c t u r a l l y different molecules w i t h e q u a l potencies

prefer

conformations i n w h i c h v e r y s i m i l a r patterns o f c h a r g e d atoms are m a d e a v a i l a b l e , lends s u p p o r t to t h e relevance.

I t has b e e n suggested that t h e

d r u g m o l e c u l e forms a p r e l i m i n a r y w e a k b o n d w i t h t h e receptor w h i l e i n t h e p r e f e r r e d c o n f o r m a t i o n , f o l l o w e d b y a m o r e i n t i m a t e a n d stronger association i n w h i c h b o t h d r u g a n d receptor conformations (50).

are altered

T h e stereoselective " r e c o g n i t i o n " o f the d r u g , h o w e v e r , occurs d u r

i n g the p r e l i m i n a r y event, p r i o r to a n y m u t u a l p e r t u r b a t i o n . M u c h r e m a i n s to b e e x p l o r e d c o n c e r n i n g these events; h o w e v e r , results t o date suggest that t h e p r e s u m p t i o n o f t h e i m p o r t a n c e o f p r e f e r r e d c o n f o r m a t i o n is a u s e f u l o p e r a t i o n a l hypothesis. F i n a l l y , M O p r e d i c t i o n s s h o u l d b e c o n s i d e r e d as a n a d j u n c t t o t h e d r u g d e s i g n a n d m e c h a n i s m i n t e r p r e t a t i o n process.

T h e calculations

s h o u l d a l w a y s b e b a s e d o n reasonable c h e m i c a l structures a n d processes, a n d t h e results a n d i n t e r p r e t a t i o n s s h o u l d a l w a y s b e v i e w e d i n t h e l i g h t of b i o l o g i c a l r e a l i t y o r reasonable m e c h a n i s m s . T h e M O t h e o r y c a n thus be a p o w e r f u l servant to t h e m e d i c i n a l c h e m i s t o r c h e m i c a l p h a r m a cologist i n his search f o r b i o l o g i c a l explanations a n d n e w drugs.

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RECEIVED May 10,

1971.



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Molecular Orbital Studies of Biological Molecule Conformations

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