Computer-Assisted Drug Design - American Chemical Society

19 Conformational Analysis: A Module in a Program for the Design of Biologically Active Compounds A. J. STUPER, T. M. DYOTT, and G. S. ZANDER

Downloaded by UNIV LAVAL on July 12, 2016 | http://pubs.acs.org Publication Date: November 28, 1979 | doi: 10.1021/bk-1979-0112.ch019

Research Laboratory, Rohm and Haas Company, Spring House, PA 19477

The last decade has seen considerable progress made in understanding the relationship between chemical structure and biological activity. Despite this progress our ability to design active molecules is still quite unsophisticated. While we are certainly unable to a priori, design molecules possessing specific biological properties, we are able to identify several factors which govern this action. These are: 1) steric properties 2) transport properties 3) reactivity Certainly each factor does not operate independently of the others. Reactivity is influenced by the steric properties of a molecule, as is transport. Also these factors do not directly address the possible metabolic fate of a compound. However, such a division does allow us to concentrate on specific aspects of the problem and to direct our synthetic efforts accordingly. How then does this relate to the practical problem of developing new, effective, and safe drugs or other biologically active materials? There are certainly two ways to approach the problem. We can assume that by its nature the design problem i s i n t r a c t a b l e t o any t h e o r e t i c a l approach and t h e r e f o r e synthesize as many v a r i a n t s of a lead compound or t e s t as many new compounds as we can economically a f f o r d . For t h i s course o f a c t i o n , our success w i l l be a f u n c t i o n o f luck aided by i n t u i t i o n . On the other hand, we can take the approach that c o n t r o l o f those factors e f f e c t i n g a c t i v i t y w i l l i n c r e a s e the p r o b a b i l i t y o f reaching our goal. While the f a c t o r s i n f l u e n c i n g a c t i v i t y are not a l l under our c o n t r o l , an attempt t o c o n t r o l as many as p o s s i b l e w i l l r e duce the a r b i t r a r y nature inherent i n the f i r s t approach. Taking the l a t t e r approach there are two ways to guide our s y n t h e t i c e f f o r t s . To optimize the a c t i v i t y o f a compound we can attempt t o f i n d mathematical models which r e l a t e changes i n the above f a c t o r s t o changes i n the observed a c t i v i t y . We can then 0-8412-0521-3/79/47-112-383$08.00/0 ©

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.

COMPUTER-ASSISTED DRUG DESIGN


384

use these models t o a s s i s t us i n determining which analoges h o l d out the most promising chance f o r i n c r e a s e d a c t i v i t y . T h i s process i s w e l l documented, having been e x t e n s i v e l y developed by Hansch and co-workers (1,2). On the other hand, we may d e s i r e a compound which has the a c t i v i t y of a p a r t i c u l a r l e a d , but i s o f apparently d i f f e r e n t s t r u c t u r e . That i s a new l e a d . In t h i s case we would t r y t o design compounds which possess d i f f e r e n t chemical s t r u c t u r e s but maintain i d e n t i c a l s t e r i c , t r a n s p o r t , and r e a c t i v i t y p r o p e r t i e s . I t was f o r t h i s purpose that we have developed a computerized t o o l , c a l l e d MOLY, which can a s s i s t i n the molecular design problem. In t h i s paper we w i l l b r i e f l y review what t h i s system i s and d e t a i l our e f f o r t s t o parameterize the conformational a n a l y s i s s e c t i o n o f MOLY. Overview o f the MOLY Program We present t h i s s e c t i o n t o provide an understanding o f the context w i t h i n which the conformation a n a l y s i s program operates. MOLY i s an i n t e r a c t i v e system which employs computer graphics as the means o f communicating i t s r e s u l t s t o the s c i e n t i s t . The system has the f o l l o w i n g c h a r a c t e r i s t i c s : 1. 2. 3. 4. 5.

l a r g e |>1000K b y t e s ] modular command d r i v e n c o n s i d e r a b l e user prompting h i g h l y graphics o r i e n t e d

Figure 1 shows the system's a r c h i t e c t u r e . The main program, r e f e r r e d to as the d r i v e r , deciphers the user's d i r e c t i o n s and c a l l s the appropriate module. This module then i n t e r a c t s with the user to perform a s p e c i f i c task. There are seven major modules whose primary f u n c t i o n s a r e : 1. INPUT

- Input molecules by drawing them on the screen o f the graphics t e r m i n a l .

2. MODEL

- B u i l d a reasonable three dimensional model o f a molecule.

3.

- Perform a conformation

CONFOR

analysis.

4. ANALYZE - Prepare contour maps o f energy and p o p u l a t i o n as a f u n c t i o n o f r o t a t i o n about one o r two bonds. 5.

LOGP

- Estimate the value of the o c t a n o l / water p a r t i t i o n c o e f f i c i e n t .



19.

STUPER E T A L .

Conformational

Figure 1.

Analysis

Architecture of MOLY


385

COMPUTER-ASSISTED

386

6. FORMAT

DRUG DESIGN

- Provide an i n t e r f a c e between the i n t e r a c t i v e program and batch v e r s i o n s of quantum mechanical programs.


7. COMPARE - Provide v i s u a l comparisons between d i f f e r e n t molecules by matching s e l e c t e d p o r t i o n s of t h e i r s t r u c t u r e s . In a d d i t i o n MOLY contains a l a r g e number of u t i l i t y programs which allow f o r e f f i c i e n t molecular s t o r a g e , r e t r i e v a l , o r i e n t a t i o n and d i s p l a y . The system i s w r i t t e n e n t i r e l y i n FORTRAN and executes on an IBM 370/158 under the MVS o p e r a t i n g system and the TSO t i m e - s h a r i n g system. User i n t e r a c t i o n i s v i a a T e k t r o n i x 4006 or 4010 graphics t e r m i n a l . Hard copy c a p a b i l i t i e s are prov i d e d v i a T e k t r o n i x photocopiers as w e l l as a Calcomp d i g i t a l plotter. The Conformation A n a l y s i s Module The e s s e n t i a l problem i n conformational a n a l y s i s i s t o f i n d the proper s p a t i a l o r i e n t a t i o n of a molecule's atoms. I f we cons i d e r the bond lengths and bond angles to be f i x e d then shape i s e n t i r e l y determined by the r o t a t i o n about s i n g l e bonds. The approximation of the f i x e d nature of bond lengths and angles i s w e l l accepted. These r e l a t i o n s are not s i g n i f i c a n t l y a l t e r e d by c r y s t a l or s o l v a t i o n f o r c e s . T o r s i o n a l i n t e r a c t i o n s which are of r e l a t i v e l y low energy are o f t e n d r a s t i c a l l y a l t e r e d by such f o r c e s . By c a l c u l a t i n g the molecular energy at a l l p o s s i b l e p o s i t i o n s of a l l r o t a t a b l e bonds, we are able to determine the r o t a t i o n angle at which the energy i s a minimum. The minimum energy conformations are those i n which the molecule i s most l i k e l y to be found i n the gas phase. I f these minima are s u f f i c i e n t l y deep, then i t i s l i k e l y that the same conformations w i l l be observed i n s o l u t i o n or the c r y s t a l l i n e s t a t e (3). The t o r s i o n a l angles i n the compounds which we s h a l l discuss w i l l be defined more p r e c i s e l y l a t e r . Here we s h a l l r e c a l l only that the t o r s i o n a l angle T about the Bond B-C i n the sequence of atoms A-B-C-D i s the angle through which the f a r bond C-D i s r o t a t e d r e l a t i v e to the near bond A-B. The c i s p l a n e r p o s i t i o n of bonds A-B and C-D represent a T = 0°.



19.

STUPER E T A L .

Conformational

Analysis

387

T o r s i o n a l angles are considered p o s i t i v e f o r right-handed r o t a t i o n ; when l o o k i n g along the bond B-C, the f a r bond C-D r o t a t e s clockwise r e l a t i v e to the near bond A-B. A l t e r n a t i v e l y , the p o s i t i v e angles are defined as 0° to 180°, measured f o r a c l o c k wise r o t a t i o n , and negative angles as 0° t o -180°, measured f o r a counterclockwise r o t a t i o n . Since the valence of an atom i s g e n e r a l l y g r e a t e r than two the sequence of atoms A-B-C-D may be non-unique. However, i t i s s u f f i c i e n t to designate any four atoms which w i l l be used to d e f i n e the t o r s i o n a l angles used i n any p a r t i c u l a r problem. As e x p l a i n e d above, a Τ of 0° i s always the c i s p l a n e r arrangement of the atoms designated as d e f i n i n g the t o r s i o n a l angle. Conformational a n a l y s i s presents a c o m b i n a t o r i a l problem. An a n a l y s i s i n v o l v i n g 360 degree r o t a t i o n s i n D degree i n c r e ments about Ν d i f f e r e n t bonds r e q u i r e s the examination of (360/D)^ conformations. The number of conformations i n c r e a s e s e x p o n e n t i a l l y with the number of bonds b e i n g r o t a t e d . For ex ample, i f D i s 30 degrees and Ν i s 2 then only 144 conformations must be examined, but i f Ν i s i n c r e a s e d to j u s t 5 the number of conformations jumps to 248,832. The sheer magnitude of such a problem r u l e s out even the f a s t e s t quantum mechanical technique. E m p i r i c a l methods are the only p r a c t i c a l means of examining such a l a r g e number of conformations. In our system, conformational a n a l y s i s i s performed by the module CONFOR. An a n a l y s i s i s defined by s p e c i f y i n g the bonds to' r o t a t e , the increment of r o t a t i o n , and the t o t a l number of degrees to r o t a t e . On the b a s i s of t h i s i n f o r m a t i o n the program c a l c u l a t e s the number of conformations which would r e s u l t . I f the problem i s too l a r g e to be done i n t e r a c t i v e l y (>5 CPU minutes), the problem can be s i m p l i f i e d or CONFOR can be used to i n i t i a t e a background batch job which w i l l perform the a n a l y s i s . In e i t h e r event once an a n a l y s i s i s complete the s c i e n t i s t can ask f o r the low energy conformations, look at energy contour maps, p l a c e the molecule i n v a r i o u s conformations f o r v i s u a l i n s p e c t i o n , etc. In CONFOR, conformation energy i s broken i n t o four terms. Ε where:

= E - + E -, + Ε,, ,+ Ε vdw coul hbond conj

conf E c

E

E

o

n

f

vdw

^

s

t

i s

n

e

r e l a t i v e energy of the conformation

t l i e

V

a

n

c

o

e r

W

a

^ interactions coul * * l ^ l S

t

i e

u

o

m

:

a

c

l

s

t e r m

>

accounting f o r s t e r i c

i n t e r a c t i o n term, accounting f o r

p a r t i a l charge i n t e r a c t i o n s hbond S bond term Ε . i s the conjugated bond term accounting f o r t o r s i o n a l preferences due t o conjugation E

i S

t

h

e

h

v

d

r

o

e

n


388


The exact mathematical form of each energy term i s given i n Table I. j * * standard 6-12 Lennord-Jones p o t e n t i a l func tion. Ε ^ i s the c l a s s i c a l coulombic p o t e n t i a l f u n c t i o n . The dielectrîc constant of the s o l v e n t , ε, can be s p e c i f i e d by the s c i e n t i s t , otherwise i t d e f a u l t s to a value of 3 . 5 . Ehbond the hydrogen bond p o t e n t i a l f u n c t i o n developed by Scheraga et a l (4). T h i s f u n c t i o n has no angular dependence u n l i k e the func t i o n developed by Hopfinger et a l (5) which i n our experience i s overly r e s t r i c t i v e . The Ε . term was developed by us i n the course of t h i s work. I t i s an attempt to take i n t o account the t o r s i o n a l bar r i e r s caused by i n t e r a c t i o n of adjacent π systems and/or lone pairs. Such systems, e.g., amides, benzoic a c i d s , and dienes, show a preference f o r p l a n a r conformations which maximize con j u g a t i o n . The b a s i c form of the f u n c t i o n i s the standard cosine r e l a t i o n s h i p f r e q u e n t l y used f o r t o r s i o n a l energy: E

s

V

(

t

i e

w

U


i s

E

conj

where:

E

h

=

Bd-cos(N0)3

Β i s h a l f the b a r r i e r height Ν i s a symmetry constant, u s u a l l y 2 θ i s the t o r s i o n a l angle a

s

a

v

a

l

u

e

f

o

r

t

n

e

conj °f 0·0 p r e f e r r e d values of θ and i n creases i n a smooth s i n u s o i d a l manner to a maximum of +2B as θ deviates from the p r e f e r r e d values. I f , however, e i t h e r or both of the systems i n conjugation are f u r t h e r conjugated, as i s f o r example a benzamide, where the carbonyl i s conjugated with both the amide n i t r o g e n and the phenyl r i n g , the e f f e c t i v e b a r r i e r i s decreased v i a two mechanisms : 1. The energy gained from conjugation i n i t i a l l y i s l e s s , i . e . , i n the case of the benzamide, s i n c e the carbonyl i s conjugated with the phenyl i t cannot conjugate as s t r o n g l y with the n i t r o g e n . 2. Energy l o s t by the r e d u c t i o n of conjugation due to r o t a t i o n about one bond can be p a r t i a l l y r e covered by increased conjugation with the other conjugated groups. This e f f e c t , however, i s dynamic. For example, as the phenyl r i n g r o t a t e s out of conjugation w i t h the amide the t o r s i o n a l b a r r i e r about the amide bond returns to f u l l s t r e n g t h . Thus the e f f e c t i v e b a r r i e r to r o t a t i o n about a conjugating bond i s de pendent on: 1. 2. 3. 4.

11

the "normal b a r r i e r f o r such a bond any a d d i t i o n a l conjugated groups t h e i r conjugative s t r e n g t h t h e i r r e l a t i v e conformation


19.

STUPER E T A L .

Table 1.

Conformational

Mathematical Form of P o t e n t i a l Functions

Nonbonded

*v4,- V - U C

«:

where

Coulombic


A

] / d 6

r e p u l s i v e constant dependent on atoms i , j a t t r a c t i v e constant dependent on atoms i , j E u c l i d i a n distance between atoms i and j

coul

*1

d hbond

where

Ε r

Γ

Rotational Barriers

d 6

332.0 J

where

H-bond

389

Analysis

E

o

ΗΧ

tor

d d i e l e c t r i c constant p a r t i a l atomic charge on atom i E u c l i d i a n distance between atoms i and j E [ r / r ] 1 2 - 2.0E[r /r ]10 D

H X

o

H X

energy constant dependent on type of atoms p a r t i c i p a t i n g i n the hydrogen bond i n t e r n u c l e a r distance parameter dependent on type of atoms E u c l i d i a n distance between donor and acceptor atoms cos(N0 )] k

n

k 1 - Σ i*k

B.(l+cos(N0.)) —

— n

k

2-Σ

B

±

i=l where

B

B

e

9

n

k = the e f f e c t i v e b a r r i e r to r o t a t i o n about the bond of i n t e r e s t the non-conjugated b a r r i e r to r o t a t i o n about the bond of i n t e r e s t i - the non-conjugated b a r r i e r to r o t a t i o n about the i t h conjugated bond k = the t o r s i o n a l angle f o r the bond being rotated i - the t o r s i o n a l angle f o r the conjugate bonds k = number of bonds conjugated w i t h bond k Ν = a symmetry f a c t o r


390


CONFOR a u t o m a t i c a l l y takes a l l of these f a c t o r s i n t o account. I t i n i t i a l l y f i n d s a l l conjugating bonds and assigns t h e i r "normal" b a r r i e r values and symmetry constants. These values are shown t o the s c i e n t i s t who can s p e c i f y a l t e r n a t i v e values. As the molecule i s b e i n g stepped through various conformations, the e f f e c t i v e t o r s i o n a l b a r r i e r s of any conjugating bonds are r e c a l c u l a t e d and then used t o c a l c u l a t e Ε . v i a the formulas given i n Table I.


P a r a m e t e r i z a t i o n of the Conformational A n a l y s i s Module Before we can use the r e s u l t s of conformational a n a l y s i s to p r e d i c t the s t e r i c c o n s t r a i n t s f o r a drug we must be reason ably c e r t a i n that the method i s p r o p e r l y parameterized. Our major concern i s that the minima i n d i c a t e d are l o c a t e d p r o p e r l y and the contour energy maps produced have a reasonable shape. T h i s requirement i s r a t h e r broad. Our experience has been that the accuracy of e m p i r i c a l f u n c t i o n s s u f f i c e f o r systems which show l i t t l e or no s t a b i l i z a t i o n due to resonance or other types of e l e c t r o n i c interchange. There are s e v e r a l ways to approach the p a r a m e t e r i z a t i o n problem. Previous groups have used comparisons to c r y s t a l pack i n g as a guage f o r the non-bonded i n t e r a c t i o n s ( 6 ) . They then f i n e tune the program u s i n g comparisons t o a l l valence MO c a l c u l a t i o n s . We have chosen much the same route. Our f i n e t u n i n g was done by comparing our r e s u l t s t o those obtained using the PCILO technique of Pullman (7-9). We chose t h i s technique be cause of i t s accuracy and the a v a i l a b i l i t y of a l a r g e number of c a l c u l a t i o n s f o r v a r i o u s s m a l l molecules. In order to define the f a c t o r s i n v o l v e d i n p a r a m e t e r i z i n g the non-bonded p o t e n t i a l f u n c t i o n , i t i s necessary t o describe the f u n c t i o n a l approximations used. As have o t h e r s , we used the Lennord-Jones 6-12 p o t e n t i a l as the b a s i s f o r t h i s i n t e r a c t i o n . The form of t h i s i s : Ε

vw

= B/d

1 2

- A/d

6

(1)

E i s the energy of the i n t e r a c t i o n i n K c a l , d i s the d i s t a n c e , i n angstroms, between the i n t e r a c t i n g atoms, A and Β are con s t a n t s which depend on the type of atoms i n v o l v e d i n the i n t e r a c t i o n . A t y p i c a l p o t e n t i a l i s shown i n F i g u r e 2. At l a r g e distances there i s e s s e n t i a l l y no c o n t r i b u t i o n to the conforma t i o n a l energy, but as the distance decreases t h i s energy becomes i n c r e a s i n g l y a t t r a c t i v e . With a f u r t h e r decrease i n distance the atoms get too c l o s e and q u i t e r a p i d l y s t a r t to r e p e l l each other. There are two f a c e t s to the Lennord-Jones p o t e n t i a l f u n c t i o n which i n t e r e s t us, the e q u i l i b r i u m distance d and the w e l l depth E . These parameters are r e l a t e d to A and Β by: w

Q

0


STUPER E T A L .

Conformational

Analysis


19.


391



392

Figure 3.

Thirteen molecules used for comparison to PCILO



STUPER E T A L .

L.

Conformational

PSEUOQflMTLEINE

Analysis

M

PSEUDOLIOOCFIINE


394

COMPUTER-ASSISTED

A

(2)

Β

(3)

Our i n i t i a l s e t t i n g s f o r these constants were taken from the l i t e r a t u r e (10,11). U n l i k e the l i t e r a t u r e references we do not d i f f e r e n t i a t e ~ t n e atoms a c c o r d i n g t o h y b r i d i z a t i o n . The l i t e r ature values thus served as an i n i t i a l approximation. In order to develop a c o n s i s t e n t set of constants we compared our c a l c u l a t i o n s on the t h i r t e e n molecules i n F i g u r e 3 to those obtained by PCILO. We then adjusted our E and d values to o b t a i n r e s u l t s which were c o n s i s t e n t with the PCILO c a l c u l a t i o n s . Table I I l i s t s the values of A, B, d , and Ε which r e s u l t e d from t h i s comparison. Note that i t was necessary to d i f f e r e n t i a t e between aromatic and non-aromatic hydrogens. This parameterization i s only a p p r o p r i a t e f o r H, C, 0, N, and S. The values f o r the other elements l i s t e d represent the i n i t i a l approximations. Our d values are a l l somewhat h i g h e r than those used by Hopfinger (10) and s m a l l e r than those used by Scheraga (11). The d i f f e r e n c e between our values and H o p f i n g e r s i s proEably due to our not d i v i d i n g the atoms a c c o r d i n g to valence. The Scheraga values are higjtier because the minimum energy d i s t a n c e s are based upon contact d i s t a n c e s somewhat l a r g e r than the Van der Waals contact distance. Q


DRUG DESIGN

Q

Q

1

We have reproduced s e v e r a l contour maps t o demonstrate the degree of comparison between PCILO and CONFOR. These p l o t s are shown i n F i g u r e s 4 t h r u 8. To generate these maps the molecules were p l a c e d i n the geometeries s p e c i f i e d by Pullman (7-9) and the bonds i n d i c a t e d i n F i g u r e 3 were r o t a t e d . The reference atoms f o r the t o r s i o n a l angles those used by Pullman. Partial atomic charges f o r use i n the Coulombic p o t e n t i a l f u n c t i o n were obtained from CNDO c a l c u l a t i o n s . The PCILO contour maps r e p r e sent c a l c u l a t i o n s having a r e s o l u t i o n of 30 degrees about each bond. Our maps were generated u s i n g r o t a t i o n a l increments of 10 degrees. In general the agreement between the two methods was q u i t e c l o s e . Phenethylamine (Figure 3a) and Pseudoprocaine (Figure 3k) are t y p i c a l examples of c a l c u l a t i o n s which compare q u i t e c l o s e l y . Both the l o c a t i o n o f the minima and the o v e r a l l shape o f the map are very c l o s e to those obtained by PCILO. The map f o r Ephedrine (Figure 3b) has the same general shape; however, the s t a b i l i z a t i o n at T 2 - 60 degrees i s more pronounced than that shown by PCILO. A l s o , the minima f o r T i = ± 60, T = 0 are about 1 K c a l h i g h e r than that found by PCILO. I t i s not c l e a r why we see a l a r g e r s t a b i l i z a t i o n at Τχ = ± 60, T = 60. T h i s could be a r e s u l t of improper non-bonded terms. I t may a l s o be a f u n c t i o n of the d i f f e r e n c e i n the r e s o l u t i o n of the two maps. A s i m i l a r d i f f e r e n c e i s seen i n the map f o r Norephedrine (Figure 3d). Our c a l c u l a t i o n s show that at a T = ± 60, T = 60, there i s a r e g i o n of s t a b i l i t y . F i g u r e 9 shows three views of 2

2

x


2

19.

STUPER E T A L .

Table I I .

Conformational

395

Analysis

Values f o r the Nonbonded P o t e n t i a l Function


Hydrogen

A

Η 70.353

C 175.387

Ν 129.6811

Ρ 264.8311

0 123.7239

S 289.9912

Β

6281.149

33004.1

24024.57

78276.24

17088.45

95562.36

do

2.373

2.687

2.68

2.897

2.55

2.95

Eo

-0.197

-0.233

-0.175

-0.224

-0.225

-0.220

A

F 79.67815

Cl 272.4885

Br 299.1173

I 437.8515

AH 32.80541

Β

9336.187

80706.48

88410.22

166418.3

1217.415

do

2.783

2.898

2.897

3.021

2.05

Eo

-0.170

-0.230

-0.253

-0.288

-0.221

Carbon

A

H 175.387

C 522.0883

Ν 502.2265

Ρ 875.9980

0 446.1175

S 998.1056

Β

33004.1

240791.7

190507.2

616858.8

132680.5

680474.6

do

2.687

3.12

3.02

3.348

2.90

3.33

Eo

-0.233

-0.283

-0.331

-0.311

-0.375

-0.366

A

F 264.9297

Cl 906.5424

Br 1043.719

I 1475.163

AH 175.3848

Β

99698.52

636883.0

767148.0

1346600.

33004.10

do

3.016

3.346

3.372

3.496

2.687

Eo

-0.176

-0.323

-0.355

-0.404

-0.233


COMPUTER-ASSISTED DRUG

396

Table I I .


DESIGN

(cont'd.)


Nitrogen

A

Η 129.6811

C 502.2265

Ν 337.3978

Ρ 741.0352

0 383.3762

S 934.8268

Β

24024.57

190507.2

130547.3

435819.9

128927.4

483352.4

do

2.68

3.02

3.03

3.250

2.96

3.18

Eo

-0.175

-0.331

-0.218

-0.315

-0.285

-0.452

A

F 224.7778

Cl 752.4295

Br 854.4915

I 1216.361

AH 129.6811

Β

56642.43

450756.5

529098.3

941178.8

24024.57

do

2.82

3.26

3.277

3.401

2.68

Eo

-0.223

-0.314

-0.345

-0.393

-0.175

Phosphorous

A

H 264.8311

C 875.9980

Ν 41.0352

Ρ 1474.461

0 725.8096

S 1562.526

Β

78276.24

616858.8

435819.9

1709147.

343864.0

1436368.

do

2.897

3.348

3.250

3.638

3.13

3.50

Eo

-0.225

-0.311

-0.315

-0.318

-0.383

-0.425

A

F 477.570

Cl 1032.84

Br 1420.615

I 1994.231

AH 264.8311

Β

331501.9

716969.2

1233586.

2138148.

78276.24

do

3.34

3.56

3.467

3.591

2.897

-0.172

-0.372

-0.409

-0.465

-0.224

E

o


19.

STUPER E T A L .

Table I I .

Conformational

Analysis

397

Values f o r the Nonbonded P o t e n t i a l Function (cont'd.)


Oxygen

A

Η 123.7239

C 446.1175

Ν 383.3762

Ρ 725.8096

0 347.0114

S 776.8652

Β

17088.45

132680.5

128927.4

343864.0

87258.63

331604.2

do

2.55

2.90

2.96

3.13

2.82

3.08

Eo

-0.225

-0.311

-0.285

-0.383

-0.345

-0.455

A

F 222.7845

Cl 743.9333

Br 873.6900

I 1244.813

AH 132.7183

Β

49239.03

368957.9

462066.7

825990.9

19571.27

do

2.76

3.16

3.192

3.315

2.58

Eo

-0.252

-0.375

-0.413

-0.469

-0.225

Sulfur H

C

Ν

Ρ

0

S

Α Ι 289.9912

998.1056

934.8268

1562.526

776.8652

1683.851

Β

95562.36

680474.6

483352.4

1436368.

331604.2

157683.0

d

0

2.95

3.33

3.18

3.50

3.08

3.5

E

0

-0.220

-0.366

-0.452

-0.452

-0.455

-0.458

F A I 474.7878

Cl 1609.260

Br 1561.998

I 2189.843

AH 289.9912

Β

231917.1

1610520.

1379998.

2383406.

95562.36

d

0

3.15

3.55

3.477

3.600

2.95

E

0

-0.243

-0.402

-0.442

-0.503

-0.220


398


Table I I .


(cont'd.)

Florine


H

C

Ν

Ρ

0

S

79.67815

264.9297

224.7778

477.570

222.7845

474.7878

9336.187

99698.52

56642.43

331501.9

49239.03

231917.1

2.783

3.016

2.82

3.34

2.76

3.15

-0.170

-0.176

-0.223

-0.172

-0.252

-0.243

F

Cl

Br

I

AH

135.7213

456.2523

381.9460

544.8931

79.10228

37137.62

295690.5

187993.1

337396.0

9201.722

2.86

3.30

3.154

3.277

2.48

-0.124

-0.176

-0.194

-0.220

-0.170

Chlorine H

C

Ν

Ρ

0

S

272.4885

906.5424

752.4295

1032.84

743.9333

1609.260

80706.48

636883.

450756.5

716969.2

368957.9

1610520.

2.898

3.346

3.26

3.56

3.16

3.55

-0.230

-0.323

-0.314

-0.372

-0.375

-0.402

F

Cl

Br

I

AH

A I 456.2523

788.0722

1068.890

1503.2822

272.4885

Β

295690.5

510738.3

855184.3

1486748.

80706.48

d

Q

3.30

3.70

3.420

3.543

2.898

E

0

-0.176

-0.304

-0.334

-0.380

-0.230


19.

STUPER E T A L .

Table I I .

Conformational

Analysis

399

Values f o r the Nonbonded P o t e n t i a l F u n c t i o n (cont'd.)


Bromine

A

Η 299.1173

C 1043.719

Ν 854.4915

Ρ 1420.615

0 873.6900

S 1561.998

Β

88410.22

767148.0

529098.3

1233586.

462066.7

1379998.

do

2.897

3.372

3.277

3.467

3.192

3.477

Eo

-0.253

-0.355

-0.345

-0.409

-0.413

-0.442

A

F 381.9460

Cl 1068.890

Br 1388.129

I 1938.128

AH 299.1173

Β

187993.1

855184.3

1309037.

2246615.

88410.22

do

3.154

3.420

3.515

3.638

2.897

Eo

-0.194

-0.334

-0.368

-0.418

-0.253

Iodine

A

H 437.8515

C 1475.163

Ν 1216.361

Ρ 1994.231

0 1244.813

S 2189.843

Β

166418.3

1346600.

941178.8

2138148.

825990.9

2383406.

do

3.021

3.496

3.401

3.591

3.315

3.600

Eo

-0.288

-0.404

-0.393

-0.465

-0.469

-0.503

A

F 544.8931

Cl Br 1503.2822 1938.128

I 2693.000

AH 437.8515

Β

337396.0

1486748.

2246615.

3816973.

166418.3

do

3.277

3.543

3.638

3.762

3.021

Eo

-0.220

-0.380

-0.418

-0.475

-0.288




400

Table I I .


(cont'd.)

AH

A

Η 32.80541

C 175.3848

Ν 129.6811

Ρ 264.8311

0 132.7183

S 289.9912

Β

1217.415

33004.10

24024.57

78276.24

19571.27

95562.36

do

2.05

2.687

2.68

2.897

2.58

2.95

E

-0.221

-0.233

-0.175

-0.224

-0.225

-0.220

A

F 79.10228

Cl 272.4885

Br 299.1173

I 437.8515

AH 22.22401

Β

9201.722

80706.48

88410.22

166418.3

629.9831

do

2.48

2.898

2.897

3.021

1.96

Eo

-0.170

-0.230

-0.253

-0.288

-0.196

G



ez.ao

-]

a

I—»



ζ:

Ο

Ο

I

a

>

ι

8

Conformational

Analysis


STUPER E T A L .



Figure 9.

View of norephedrine showing the lack of any replusive interactions


19.

STUPER E T A L .

Conformational

Analysis

407

t h i s c o n f i g u r a t i o n . You w i l l note that there are no obviously r e p u l s i v e i n t e r a c t i o n s . I t appears that PCILO simply f i n d s the a l t e r n a t i v e s t a t e s to be more a t t r a c t i v e than does our method. The map f o r Sympath-1 (Figure 3g) appears to l o c a t e the minima p r o p e r l y , however, the shape i s somewhat d i f f e r e n t from that c a l c u l a t e d by PCILO. We show a l a r g e r r e p u l s i o n about the center of the map. This could be a f u n c t i o n of the r e s o l u t i o n used i n the PCILO c a l c u l a t i o n s , but more l i k e l y i n v o l v e s b a s i c d i f f e r e n c e s between the two methods. For our purposes t h i s map i s s u f f i c i e n t l y accurate.


Comparisons f o r Other Compounds For the purpose of t e s t i n g the a p p l i c a b i l i t y of the CONFOR r o u t i n e to s t r u c t u r a l types other than those used i n the par a m e t e r i z a t i o n , we have performed many c a l c u l a t i o n s . We present three such comparisons below. A p a r t i c u l a r l y i n t e r e s t i n g set of c a l c u l a t i o n s are those we performed on the g l y c y l and v a l y l amino a c i d r e s i d u e s . Pullman has reported work on both molecules (12). In order to compare our r e s u l t s we reproduced these c a l c u l a t i o n s using the CONFOR module. Figure 10 shows a comparison of the maps f o r the g l y c y l residue. The dots on the maps represent known conformations of g l y c y l residues i n g l o b u l a r p r o t e i n s . In the case of the v a l y l residue PCILO p r e d i c t s a g l o b a l minimum where our method p r e d i c t s a maximum. As seen i n Figure 11 the conformation of the v a l y l residue i n g l o b u l a r p r o t e i n s occupies the minimum regions l o c a t e d by CONFOR and what would be a l o c a l minima i n the PCILO method. The b a r r i e r between Ψ = 270, Φ = 60 and ψ = 210, Φ = 300 shown by CONFOR i s due to the c l o s e approach of a hydrogen from the i s o p r o p y l and the oxygen of the carbonyl. The distance being only 1.81A. T h i s i s w e l l i n t o the r e p u l s i v e s t a t e of the Van der Waals i n t e r a c t i o n . Figure 12 shows one view of t h i s i n t e r a c t i o n . C l e a r l y f o r t h i s to be a minimum some s o r t of bonding must be o c c u r r i n g . Apparently PCILO i n d i c a t e s a weak hydrogen bond between t h i s hydrogen and the carbonyl oxygen. While there i s some evidence f o r the existence of C-H 0 hydrogen bonds, such bonds are experimentally observed only when the carbon a l s o bears at l e a s t one strong e l e c t r o n withdrawing group (13). I n i t i a l l y the i s o p r o p y l group was f i x e d i n the same conformation as that used by PCILO. I f we allow the i s o p r o p y l group to r e l a x i n order to remove the carbonyl-hydrogen i n t e r a c t i o n , we see a corresponding lowering of the b a r r i e r ; how ever, we are not able to obtain a l o c a l minimum i n t h i s r e g i o n . This leads us to question whether PCILO has i n d i c a t e d a r e a l i s t i c minima f o r t h i s r e s i d u e . The contour map f o r the r e l a x e d i s o p r o p y l group i s shown i n Figure 13. I t i s i n t e r e s t i n g to note that the c a l c u l a t i o n f o r the r e l a x e d s t r u c t u r e r e q u i r e d the com p u t a t i o n of 186,624 separate conformations. Such a computation i s c e r t a i n l y i m p r a c t i c l e using the more time consuming semi-




408



Figure 11.

Comparison of the energy contours calculated for the valyl residue (see Figure 4 for the meaning of the contour symbols)




410

Figure 12. View of the valyl residue showing the interaction between the carbonyl and one of the hydrogens on the isopropyl. This conformation is the minimum energy conformation as calculated by PCILO (Figure 11).


19.

STUPER E T A L .

Conformational


VR1 Τ Ι

Analysis

411

Π Τ P F P T Τ nF

ο ο

• ο

'-18D.00

-1U4.00

-108.00

-72.00

-36.00

RT0MÎ = 3

0.00

36.00

72.00

108.00

1W.0D

ΑΤ0Μ2= 4

CONTOUR VALUES ο + Χ

ζ

Υ

χ

1.00 2.00 3.00 4.00 5.00 6.00 θ.00 10.00 14.00 20.00

Figure 13. Contour map for the valyl residue calculated using CONFOR. This map was generated by allowing the isopropyl group to relax and seek a minimum energy conformation.


180.00



412

Figure 14.

Energy vs. rotational angle plot for 7,8-benzflavone. The global minimum is located at 22°, the measured angle was 23°.


19.

STUPER E T A L .

Conformational

Analysis

413

e m p i r i c a l methods. As a f i n a l example o f the u t i l i t y o f the program, we report a c a l c u l a t i o n on 7,8 benzflavone. The c r y s t a l s t r u c t u r e o f t h i s molecule has been reported by Glusker e t a l (14). F i g u r e 14 shows the map o f energy versus r o t a t i o n angle f o r the phenyl r i n g . The g l o b a l minimum was p r e d i c t e d t o be at 22 degrees. The a c t u a l value from the c r y s t a l s t r u c t u r e was 23 degrees.


Conclusions The p a r a m e t e r i z a t i o n o f our conformational a n a l y s i s program appears t o give r e s u l t s which are l a r g e l y i n agreement with the semi-empirical quantum mechanical PCILO technique. The method i s capable o f producing data which i s reasonably accurate. This t o o l promises t o be o f great a i d i n s t u d y i n g the s t e r i c r e quirements o f a drug.

Literature Cited 1. C. Hansch, "A Quantitative Approach to Biochemical Structure-Activity Relationships," Acc. Chem. Res., 2, 232 (1969). 2. W. V. Valkenburg (Ed.), "Biological Correlations - The Hansch Approach," Advances in Chemistry Series, No. 114, American Chemical Society, Washington, D.C., 1972. 3. B. Pullman and P. Courriére, "Molecular Orbital Studies on the Conformation of Pharmacological and Medicinal Compounds," the Jerusalem Symposium on Quantum Chemistry and Biochemistry V, 547 (1973). 4. R. F. McGuire, F. A. Momany and H. A. Scheraga, "Energy Parameters in Polypeptides V an Empirical Hydrogen Bond Potential Function Based on Molecular Orbital Calculations," Jour. Phys. Chem., 76(3), 375 (1972). 5. H. J. R. Weintraub and A. J. Hopfinger, "Conformational Analysis of Some Phenethylamine Molecules," J. Theor. Biol., 41, 53 (1973). 6. F. A. Momany, L. M. Carruthers, R. F. McGuire, and H. A. Scheraga, "Energy Parameters in Polypeptides VII. Geometric Parameters, Partial Atomic Charges, Nonbonded Interactions, Hydrogen Bond Interactions, and Intrinsic Torsional Potentials for the Naturally Occurring Amino Acids," Jour. Phys. Chem., 79(22), 2361 (1975). 7. J. L. Coubeils and B. Pullman, "Quantum-Mechanical Study of the Conformational Properties of Drugs with Local Anesthetic Action," Mol. Pharm. 8, 278 (1972).


414


8. J. L. Coubeils, P. Courriére and B. Pullman, "Quantum-Mechanical Study of the Conformational Properties of Sympatholytic Compounds," J. Med. Chem. 15(5), 453 (1972). 9. B. Pullman, J. L. Coubeils, P. Courrieré, and J. P. Gervois, "Quantum-Mechanical Study of the Conformational Properties of Phenethylamines of Biochemical and Medicinal Interest," Jour. Med. Chem. 15(1), 17 (1972).


10. A. J. Hopfinger, "Conformational Properties of Macromolecules," Academic Press, New York, 1973. 11. F. A. Momany, L. M. Carruthers, R. F. McGuire and H. A. Scherage, "Intermolecular Potentials from Crystal Data III. Determination of Empirical Potentials and Application to the Packing Configurations and Lattice Energies in Crystals of Hydrocarbons, Carboxylic Acids, Amines, and Amides," Jour. Phys. Chem., 78(16), 1595 (1974). 12. C. B. Anfinsen and John T. Edsall (Ed.), "Advances in Protein Chemistry," Academic Press, New York, pp. 348-562 (1974). 13. D. June Sutor, "Evidence for the Existence of C-H---O Hydrogen Bonds in Crystals." Jour. Chem. Soc., 1105 (1963). 14. Personal communication, Dr. J. P. Glusker. RECEIVED

June 8, 1979.


Computer-Assisted Drug Design - American Chemical Society

Recommend Documents