Computer-Assisted Drug Design - American Chemical Society

18

Downloaded by UNIV OF MASSACHUSETTS AMHERST on May 19, 2018 | https://pubs.acs.org Publication Date: November 28, 1979 | doi: 10.1021/bk-1979-0112.ch018

Beyond the 2-D Chemical Structure N. C. COHEN Centre de Recherches ROUSSEL-UCLAF, 102 Route de Noisy, 93230 Romainville, France

The s p e c t a c u l a r d e v e l o p m e n t o f t h e QSAR t h e o r i e s has domin a t e d t h e r e c e n t e v o l u t i o n o f d r u g - d e s i g n , and t h e c o n d i t i o n s f o r t h e u s e o f t h e s e t h e o r i e s a r e now w e l l e s t a b l i s h e d . Being cons t r u c t e d on a p a r t i c u l a r c h e m i c a l f o r m u l a , w i t h an i m p l i c i t common i n v a r i a n t c h e m i c a l s k e l e t o n , t h e s e methods a r e n o t a l w a y s a b l e t o go beyond t h e c h e m i c a l f r a m e o f t h e p a r t i c u l a r f a m i l y s t u d i e d . The r e c e n t a d v a n c e o f m o l e c u l a r b i o l o g y has w i d e n e d t h e c l a s s i c a l h o r i z o n s o f d r u g r e s e a r c h w h i c h has been c a r r i e d o u t u n t i l now on m a i n l y t w o - d i m e n s i o n a l l i n e s , a n d b a s e d on t h e s y n t h e s i s o f c h e m i c a l a n a l o g s o f known compounds. T h i s a d v a n c e i s due t o t h e discovery o fthe three dimensional s p e c i f i c i t y o f molecular i n t e r a c t i o n s w h i c h i s a f u n d a m e n t a l key t o t h e u n d e r s t a n d i n g o f l i f e processes. The c o n c e p t s o f m o l e c u l a r r e c o g n i t i o n a n d d i s c r i m i n a t i o n c o n s i d e r e d i n t h e l i g h t o f d r u g r e s e a r c h a l l o w one t o go beyond t h e c l a s s i c a l d r u g m a n i p u l a t i o n and o p t i m i z a t i o n . Geometr i c a l and a s s o c i a t e d e l e c t r o n i c p r o p e r t i e s a r e o f g r e a t importance t o t h i s new a p p r o a c h . New T r e n d s F o r t h e c o n c e p t i o n o f new m o l e c u l a r s t r u c t u r e s i t i s f i r s t n e c e s s a r y t o be a b l e t o e v a l u a t e t h e g e o m e t r i c a l p r o p e r t i e s o f reference molecules. T h e o r e t i c a l c a l c u l a t i o n s o f conformations a r e now a c c u r a t e enough s o t h a t t h i s p o i n t c a n be t a k e n as r e a d even f o r m o l e c u l e s n o t y e t s t u d i e d e x p e r i m e n t a l l y . W i t h t h e a i d o f t h e s e now c l a s s i c a l t e c h n i q u e s t h e d r u g - d e s i g n e r c a n go f u r t h e r and a d d r e s s h i m s e l f t o t h e t h r e e f o l l o w i n g f u n d a m e n t a l i t e m s : 1-

How t o r e v e a l , what t h r e e d i m e n s i o n a l s t r u c t u r a l e n t i t i e s (pharmacophore) a r e r e s p o n s i b l e f o r t h e b i o l o g i c a l p r o p e r t i e s o f a known a c t i v e compound, a n d what c o u l d be t h e a c t i v e c o n f o r m a t i o n o f t h i s compound, i f more t h a n one c o n f o r m e r i s p r o b a b l e .

2.

How t o e v a l u a t e t o what e x t e n t d i f f e r e n t m o l e c u l e s c a n 0-8412-0521-3/79/47-112-371$05.00/0 ©

1979 A m e r i c a n C h e m i c a l Society

Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

372

COMPUTER-ASSISTED DRUG DESIGN

m i m i c t h e s p a t i a l a r r a n g e m e n t o f atoms o f a known a c t i v e compound o r i t s p u t a t i v e p h a r m a c o p h o r e . 3.

We purpose

How t o c o n c e i v e o f a method f o r d e s i g n i n g o r i g i n a l chemic a l compounds w h i c h c o n f o r m t o t h e d e s i r e d r e q u i r e m e n t s . have d e v e l o p e d a c o m p u t e r p r o g r a m MIMETIC-GEMO, t h e o f w h i c h i s t o be o f some h e l p i n a n s w e r i n g p o i n t s 1

and


2.

Mimetic-Gemo T h i s c o m p u t e r p r o g r a m i s a b l e t o compare t h e m o l e c u l a r g e o m e t r i e s o f d i f f e r e n t m o l e c u l e s w i t h o u t any r e s t r i c t i o n s on t h e i r r e l a t i v e chemical s t r u c t u r e . The o n l y i m p l i c i t a s s u m p t i o n i s t h a t t h e compounds s t u d i e d a r e s u p p o s e d t o a c t b i o l o g i c a l l y by t h e same mechanism o f a c t i o n . The p r o g r a m i s a b l e t o compare a s e t o f a t l e a s t two m o l e c u l e s ( t h e a c t u a l v e r s i o n i s programmed f o r a maximum o f n = 6 m o l e c u l e s ) . The m o l e c u l e s a r e c o n s i d e r e d as f r e e t o move and t o m o d i f y t h e i r g e o m e t r i e s , p r o v i d e d t h a t t h e g l o b a l d e f o r m a t i o n o f each m o l e c u l e does n o t i n c r e a s e t h e t o t a l m o l e c u l a r e n e r g y by more t h a n a p r e - e s t a b l i s h e d amount ( i . 9 . 10-15 kcal/mole). A t t h e b e g i n n i n g o f t h e c a l c u l a t i o n s an i n i t i a l p o s i t i o n i s c h o s e n f o r each m o l e c u l e , t o g e t h e r w i t h t h e r e l a t i v e o r i e n t a t i o n s one t o t h e o t h e r , t h e t o t a l sum o f m o l e c u l e s f o r m i n g a set of n overlapping molecular geometries. The p a r a m e t e r used t o c h a r a c t e r i z e t o what e x t e n t t h e "mimetism" i s a c h i e v e d i s S^. t h e t o t a l exposed m o l e c u l a r a r e a o f t h i s set of overlapping molecules. The a i m o f t h e c a l c u l a t i o n s i s t o f i n d what a r e t h e g e o m e t r i e s o f each o f t h e n m o l e c u l e s w h i c h lead to a minimal value of S j . I n MIMETIC-GEMO t h e m o l e c u l a r e n e r g i e s and d e f o r m a t i o n s a r e c a l c u l a t e d u s i n g a p r e v i o u s l y d e s c r i b e d c o m p u t e r p r o g r a m (1J, w h i l e t h e m i n i m i z a t i o n i s c o n d u c t e d w i t h a s t a n d a r d r o u t i n e [2J • When t h e minimum i s r e a c h e d , i t i s i n t e r e s t i n g t o know f o r each molecule: - what i s i t s f i n a l g e o m e t r y and t h e c o r r e s p o n d i n g m o l e c u l a r energy, - what a r e t h e o v e r l a p p i n g and t h e n o n - o v e r l a p p i n g m o i e t i e s o f one compound r e l a t i v e t o t h e o t h e r s . I t i s a l s o u s e f u l t o a s c e r t a i n what a r e t h e g e n e r a l geometf e a t u r e s common t o t h e w h o l e s e t o f m o l e c u l e s s t u d i e d . The p r i n c i p l e o f m i n i m i z i n g t h e t o t a l e x p o s e d m o l e c u l a r s u r f a c e a r e a S j p a r a m e t e r i s a rough b u t p r a c t i c a l i n d e x . B e t t e r t h a n t h e manual m a n i p u l a t i o n o f a p p r o x i m a t e m o l e c u l a r m o d e l s t h i s c r i t e r i o n can be a p o w e r f u l t o o l f o r r e v e a l i n g t h e 3-D m i m e t i s m between s e v e r a l m o l e c u l e s . An example t o i l l u s t r a t e t h e rical


18.

COHEN

Beyond

the 2-D

Chemical

p o s s i b i l i t i e s o f t h i s approach

Structure

i s given

373

below.

Example


I n o u r r e s e a r c h g r o u p a p o t e n t h y p o l i p i d e m i c a g e n t has been f o u n d (compound I I I ) (3) w h i c h i s a c t i v e as t r e l o x i n a t e ( I I ) (4J and c l o f i b r a t e (I_) (J5) i n l o w e r i n g t h e t r i g l y c e r i d e and c h o l e s terol levels.

Chemical Formulas: Chemical Structures of Clofibrate (I), Treloxinate (11), and RU-25961 (III).

The two compounds JEI and I I I a r e much more p o t e n t ( i n R a t s ) t h a n t h e m a r k e t e d p r o d u c t I_. W h i l e i t i s easy t o r e c o g n i z e t h e common p - c h l o r o - p h e n o x y a c e t i c e s t e r i n a l l compounds, t h e o r i g i n o f t h e enhanced a c t i v i t i e s o f s t r u c t u r e s I_I and I I I i s q u e s t i o n a b l e and MIMETIC-GEMO w o u l d a p p e a r t o be u s e f u l f o r f i n d i n g o u t w h e t h e r t h e s e two m o l e c u l e s m i g h t n o t have more i m p o r t a n t f e a t u r e s i n common. Results H a v i n g s e p a r a t e l y c a l c u l a t e d t h e s t a b l e c o n f o r m e r s o f t h e two m o l e c u l e s (J3j), MIMETIC-GEMO c a l c u l a t i o n s w e r e t h e n p e r f o r m e d on t h e a c i d f o r m o f t h e compounds (7J, a l l o w i n g each one a t o l e r a n c e o f 15 k c a l / m o l e f o r i t s d e f o r m a t i o n s . A t t h e s t a r t i n g p o i n t t h e two p - c h l o r o - p h e n o x y g r o u p s w e r e c o i n c i d e n t and t h e more s t a b l e c o n f o r m e r was c h o s e n f o r each p r o d u c t . In this position the total s u r f a c e a r e a S j was e q u a l t o 369 A w h i l e t h e i s o l a t e d m o l e c u l e s had m o l e c u l a r e x p o s e d a r e a s o f 295 a n d 313 ft ^ t r e l o x i n a t e and RU-25961 r e s p e c t i v e l y . A f i r s t minimum was r e a c h e d when S j had d e c r e a s e d t o 341 with energies f o r the i s o l a t e d molecules (above t h e minimum t a k e n a s o r i g i n ) o f 14.6 k c a l / m o l e f o r 2

2

o

r


374


t r e l o x i n a t e and 12.2 k c a l / m o l e f o r RU-25961. D u r i n g t h e m i n i m i z a t i o n t h e ^10IC2C^CI^) t o r s i o n a n g l e o f the f r e e phenyl group o f I I I has r o t a t e d f r o m an i n i t i a l v a l u e o f 58.0 d e g r e e s t o t h e f i n a l v a l u e o f 26.8 d e g r e e s , i n d i c a t i n g t h a t a m i m e t i s m i s p o s s i b l e , w h i c h i n c r e a s e s t o w a r d t h e l o w e s t v a l u e s o f $. S t a r t i n g f r o m t h e same p o i n t f o r JEI and a c o n f o r m a t i o n o f I I I o p t i m i z e d f o r $ = 0°, a s e c o n d minimum was o b t a i n e d w i t h t h e e n e r g y v a l u e s o f 9.7 k c a l / m o l e f o r t r e l o x i n a t e and 11.2 k c a l / m o l e f o r RU-25961. The f i n a l v a l u e s o f $ and S j b e i n g r e s p e c t i v e l y -7.2 d e g r e e s and 345 A . F i g u r e 1 shows t h e o v e r l a p o b t a i n e d i n t h i s c a s e . S p a c e f i l l i n g c o m p u t e r d r a w i n g s (8) f o r each m o l e c u l e a r e shown i n f i g u r e s 2a and 2b; t h e y show how a r e m a r k a b l e m i m e t i s m i s p o s s i b l e , w h i c h was n o t a t a l l o b v i o u s f r o m t h e s e p a r a t e 2-D c h e m i c a l s t r u c t u r e s o f t h e two compounds. U s i n g s e v e r a l o t h e r s t a r t i n g p o i n t s i t was n o t p o s s i b l e t o go b e l o w t h e v a l u e s o f 341 - 345 A o f t h e S j i n d e x a l r e a d y o b t a i n e d . I t a p p e a r e d p o s s i b l e t o i m p r o v e t h e s e r e s u l t s by i n c r e a s i n g t h e energy t o l e r a n c e p e r m i t t e d t o the m o l e c u l e s d u r i n g the o p t i m i z a t i o n F o r i n s t a n c e w i t h t o l e r a n c e v a l u e s o f 25 and 40 k c a l / m o l e t h e c o r r e s p o n d i n g minimum v a l u e s o f S j were r e s p e c t i v e l y 327 A ($=9°) and 318 A ($ = -10°). E l e c t r o n i c Aspect


2

2

2

2

We have f o u n d i t u s e f u l t o have i n f o r m a t i o n on b o t h m o l e c u l a r g e o m e t r y and e l e c t r o n i c c h a r a c t e r i s t i c s i n t h e same f r a m e . For t h i s p u r p o s e we have c o n c e i v e d a " f o u r - d i m e n s i o n a l s y m b o l i s m " (9) which c o n s i s t s o f a v i s u a l i z a t i o n of the envelope o f the molecules s t u d i e d , on t h e s u r f a c e o f w h i c h e n e r g y c o n t o u r s o f t h e e l e c t r o s t a t i c m o l e c u l a r p o t e n t i a l a r e drawn. T h i s k i n d o f r e p r e s e n t a t i o n i s shown i n f i g u r e s 3a and 3b. The m o l e c u l a r e n v e l o p e i s d e f i n e d by c o n s i d e r i n g t h a t each atom has a r a d i u s R s u c h as a

where Ry^ i s t h e Van d e r Waals r a d i u s o f t h e atom, and R a c o n s t a n t v a l u e t a k e n h e r e t o 1.5 A. The e l e c t r o s t a t i c m o l e c u l a r p o t e n t i a l used i n t h e s e c a l c u l a t i o n s i s t h e c l a s s i c a l C o u l o m b i c e x p r e s s i o n o f t h e i n t e r a c t i o n o f a + 1e c h a r g e a t t h e p o i n t c o n cerned. The e l e c t r o n i c d e n s i t i e s o f t h e atoms b e i n g o b t a i n e d by e x t e n d e d H u c k e l 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 C l j y . From t h e s e d r a w i n g s i t can be s e e n t h a t t h e s i m i l a r i t i e s between t h e two molecules are not o n l y g e o m e t r i c a l but a l s o e l e c t r o n i c . The shape and t h e v a l u e s o f t h e e n e r g y c o n t o u r s a l l o w an a p p r e c i a t i o n o f t h e e x t e n t t o w h i c h t h e two compounds can be c o n s i d e r e d as m i m e t i c s . Conclusion 0

T h e s e d a t a show t h a t s i m i l a r i t i e s between c h e m i c a l compounds can e x i s t f r o m t h e p o i n t o f v i e w o f t h e m o l e c u l a r g e o m e t r y , w h i c h a r e n o t o b v i o u s f r o m t h e 2-D s t r u c t u r e s . What i s needed f o r t h e f u t u r e o f d r u g - d e s i g n i s t o d e v e l o p new o r i g i n a l m o l e c u l a r a r c h i t e c t u r e s c o n c e i v e d on t h e b a s i s o f s p a t i a l m i m e t i s m between g e o m e t r i c a l and e l e c t r o n i c f e a t u r e s .


COHEN

Beyond

the 2-D Chemical

375

Structure


18.

Figure 1.

Overlap reached after minimization of S for the acid forms of treloxinate (II) and RU-25961 (III) (S = 345 A ) T

T

2




376


COHEN

Beyond

the 2-D Chemical

Structure


18.

Figure 2b.

Three dimensional mimetism between the acid forms of RU-25961


377

378



A 0 s 40.0

Figure 3a.

TETA =-220.0

LAHDA = 240.0

ALFA s 0.0

BETA =

ro t ).0

2 OAnnc s 0.0

Envelope of the acid forms of the molecules with the energy contours (Kcal) of the electrostatic molecular potential for treloxinate


COHEN

Beyond

the 2-D Chemical

Structure


18.

Figure 3b.

Envelope of the acid forms of the molecules with the energy contours (Kcal) of the electrostatic molecular potential for RU-25961


379

380



Abstract QSAR theories are convenient for the design of new analogs of a known active compound but these theories are not always able to go beyond the chemical frame of the particular family studied. Considering structure-activity studies in the light of the three dimensional specificity of molecular interactions between drugs and receptors, conformational properties appear to be essential. To allow the design of new molecular architectures which could be able to mimic the essential features of known active compounds, i t is necessary to evaluate to what extent different molecules can mimic the spatial arrangement of atoms of a known active compound. The criterion of minimization of the total exposed molecular area of sets of overlapping molecules appears to be a powerful tool for revealing the 3-D mimetism between several molecules. During the minimization the molecules are not rigid but free to move and modify their geometries, provided that the molecular energies do not increase by more than a pre-established amount. Such calculations can reveal the biologically relevant molecular geometries and the possible associated pharmacophores. It is possible for the 3-D mimetism to be, not only geometrical but also electronic. Both properties can be visualized in a "four dimensional symbolism" which consists of a view of the envelope of the molecules studies, on the surface of which, energy contours of the electrostatic molecular potential are drawn. An example will be presented to illustrate the possibilities of this approach.

Literature Cited 1 COHEN N. C. Tetrahedron (1971) 27, 789 "GEMO, a computer program for the calculation of the preferred conformations of organic molecules." 2 Subroutine SCOOP supplied by the IBM Company. 3a CLEMENCE F., HUMBERT D. and DAGNAUX M. (1977) Belgian Patent BE 860,500. b CLEMENCE F., HUMBERT D., DAGNAUX M. and FOURNEX R. to be published. 4 GRISAR J. M., PARKER R. A., KARIYA T., BLOHM T. R., FLEMING R. W., PETROW V., WENSTRUP D. L. and JOHNSON R. G., J. Med Chem. (1972) 15, 1273 "Treloxinate and related hypolipidemic derivatives." 5 WITIAK D. T., NEWMAN H. A. I. and FELLER D. R. "Clofibrate and related Analogs. A Comprehensive Review." Marcel Dekker, New York, N.Y. 1977.


18. COHEN

Beyond the 2-D Chemical Structure

381

6 Calculated with the GENO program (ref. 1). 7 It is admitted that the active principle is the free carboxylic acid form, and we refer in all the calculations to these forms.


8 COHEN N. C. "Computer program VIF" supplied on request. 9 COHEN N. C. "Computer programs VISOPOT" unpublished work. 10 HOFFMANN R. J. Chem. Phys. (1963) 39, 1397 "An extended Hückel theory." RECEIVED

June 8, 1979.


Computer-Assisted Drug Design - American Chemical Society

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