Computer-Assisted Drug Design - American Chemical Society

Chemistry Department, University of Kansas, Lawrence, KS 66045. As even a casual ..... and to Drs. E.C. Olson, B.V. Cheney, D. Duchamp and many others...
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Quantum Pharmacology: Recent Progress and Current Status

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RALPH E . CHRISTOFFERSEN Chemistry Department, University of Kansas, Lawrence, KS 66045

As even a casual perusal of the current literature will indicate, the development of theoretical techniques and application to problems in biology in general and drug design in particular has expanded substantially in recent years. This has been due in part to the appearance of techniques and computing equipment that allow examination of large molecular systems, but has also been motivated substantially by the potential practical use of these techniques in the design of new medicinal agents. When combined with similar advances in experimental biochemistry and pharmacology, the beginnings of a new field can be identified, in which problems of interest to pharmacology can be examined at the molecular level. It is the status of these efforts that are of interest in the current symposium. More particularly, in this opening review we shall focus primarily upon the use of theoretical techniques to study problems in pharmacology. In order to produce a study of manageable size, this review will include only those studies involved with drug design per se, i.e., theoretical studies of isolated drug molecules, solvated drug molecules, or model drug-receptor interactions of potential use in the design of new medicinal agents. It will therefore omit a large number of important studies on other biological problems such as photosynthesis, the structure and function of nucleic acids, polypeptides and proteins, and many others. However, as will become apparent below, the activity in the area of "theoretical drug design" itself has been high, with significant progress occurring in several aspects. Literature Review Since the work in this area has been reviewed previously (1, 2) for the period up through the end of 1975, only studies published during 1976-1978 will be included here. In this period, 0-8412-0521-3/79/47-112-003$05.00/0 © 1979 American Chemical Society

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

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80 s t u d i e s o f i n t e r e s t t o t h i s review appeared and were found i n 13 d i f f e r e n t j o u r n a l s and books. Combined with the 130 a r t i c l e s p r i o r t o 1974 (_L) and the 24 s t u d i e s reported i n 1975 ( 2 ) , i t i s seen that over 230 s t u d i e s have now appeared i n t h i s area. The t h e o r e t i c a l techniques used f o r the s t u d i e s i n t h i s review i n c l u d e ab i n i t i o techniques (3-6_), semi-empirical techniques such as PCILO ( 7 ) , CNDO and TNDO (£, 9_), IEHT (10-12_), MINDO (13), and HMO (14), e m p i r i c a l p o t e n t i a l s (15-17), and other techniques (18-21). In a d d i t i o n , s e v e r a l review a r t i c l e s and books i n t h i s area have appeared (22-24) during t h i s p e r i o d . The 80 s t u d i e s themselves (25-104) are summarized i n Table 1, where they have been categorized~~by both the k i n d o f agents that were s t u d i e d and the methodology used. Before d i s c u s s i n g these f u r t h e r , i t i s important t o note s e v e r a l t h i n g s . F i r s t , the assignment o f a study t o a p a r t i c u l a r type o f agent f r e q u e n t l y cannot be done unambiguously due t o the f a c t that drugs f r e q u e n t l y have more than one k i n d o f a c t i v i t y . Thus, the e n t r i e s i n Table 1 may have a p p l i c a b i l i t y i n more than simply the category i n which they have been l i s t e d . A l s o , i n some cases s e v e r a l d i f f e r ent t h e o r e t i c a l techniques have been employed, i n which case a given study may have more than one entry i n Table 1. Next, i t i s important t o remember that the a c t i o n o f a drug i s determined i n general by a v a r i e t y o f f a c t o r s , i n c l u d i n g : 1. Absorption. 2. Excretion. 3. Catabolism, 4. Binding t o Plasma P r o t e i n . 5. Penetration o f the Blood-Brain B a r r i e r . 6. A f f i n i t y f o r the Receptor. 7. Intrinsic Activity. Each o f these f a c t o r s needs t o be considered i f a d e t a i l e d understanding o f drug a c t i o n i s t o be obtained. However, the theor e t i c a l s t u d i e s described i n t h i s review w i l l d e a l t y p i c a l l y with only one o r two o f the f a c t o r s described above (e.g. , receptor a f f i n i t y and/or i n t r i n s i c a c t i v i t y ) , and w i l l be o f d i r e c t a i d i n drug design only i f the other f a c t o r s have a r e l a t i v e l y constant c o n t r i b u t i o n i n the s e r i e s o f drugs s t u d i e d . Turning t o the s p e c i f i c s t u d i e s reported during 1976-78, there are s e v e r a l general comments o f i n t e r e s t . Of greatest importance among these i s the demonstrable change i n the sophist i c a t i o n o f the techniques used i n t h e o r e t i c a l s t u d i e s . For example, only 8% o f the s t u d i e s reported p r i o r t o 1975 (1) used ab i n i t i o quantum mechanical techniques , while over 25% o f the s t u d i e s reported i n the 1975-78 p e r i o d used ab i n i t i o techniques. While the use o f ab i n i t i o techniques does not per se i n d i c a t e an improvement i n the accuracy o f the r e s u l t s (due t o l i m i t e d b a s i s sets and other l i m i t a t i o n s ) , i t does i n d i c a t e that a " s t a t e - o f - t h e - a r t " that was p r e v i o u s l y thought t o be obtainable f o r " s m a l l " o r "medium-sized" chemical systems i s now a v a i l a b l e f o r use on the s u b s t a n t i a l l y l a r g e r systems o f t y p i c a l i n t e r e s t

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

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Quantum Pharmacology

Table 1. T h e o r e t i c a l Studies on Systems o f Pharmacological I n t e r e s t . Method Used Agent

IEHT

CNDO/2

INDO

PCILO

Ab I n i t i o

Other

A. Agents A f f e c t i n g Nerve Function

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1. Adrenergics 2. A n a l g e s i c s

46

68 104 80

35,66

80

30,40 34,36 , 62 ,76 . 74,75, 80,94 99 96,98

28,38 87 61,63, 78,98, 100

3. A n a l e p t i c s 84

27,31

8. Anticonvulsants and Muscle Relaxants

48

53

9. Antidepressants and Stimulants

32

4. Anaesthetics 5. A n t i - a n g i n a l Agents 6. A n t i - a n x i e t y Agents 7. Anti-arrhythmic Agents

10. A n t i p a r k i n s o n i a n Agents 11. A n t i p s y c h o t i c s 12. A n t i t u s s i v e s 13. C h o l i n e r g i c s and Anticholinergics

37

44

56

39

14. Emetics and Anti-emetics 15. Hallucinogens

97,70

J6. Hypnotics and Depressants

69

25,43, 64,71, 73,77, 85

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

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Table 1.

(cont.)

Agent

IEHT

CNDO/2

INDO

PCILO

Ab I n i t i o

Other

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B. Agents A f f e c t i n g Cardiovas c u l a r Function 1. V a s o d i l a t o r s and Vasoconstrictors

42,102

2. Hypotensive and Hypertensive Agents

45

3. Antihyperchol e s t e r o l Agents 4. Ant i coagulant s 5. Cardiac Glycosides 6. Vasopressor Agents

C. Agents A f f e c t i n g Endocrine Function 1. S t e r o i d Hormones 2. Prostaglandins 88,95

3. P o l y p e p t i d e , P r o t e i n , and Other Hormones 4. Thyroid Agents 5. Hypoglycaemic Agents

49

D. A n t i - i n f e c t i v e and Chemotherap e u t i c Agents 1. Anti-amoebic Agents 2. A n t i b i o t i c s

58

51, 101

92

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

54,60, 65 ,93

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Table 1.

7

(cont.)

Agent 3.

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IEHT

Anticancer Agents

CNDO/2

INDO

PCILO

52,57, 67,89, 90,91

Ab I n i t i o

Other

55,81, 83,90

41,86

4. A n t i f u n g a l Agents 50

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5. A n t i m a l a r i a l Agents 6. Antimycobact e r i a l Agents 7. A n t i p a r a s i t i c s 8.

Antiprotozoan Agents

9. A n t i s e p t i c s 10. A n t i v i r a l s

E.

33 59 82

Miscellaneous

1. A n t i h i s t a m i n i c and A n t i a l l e r genic Agents and Histamine

26,29, 72

2. Carbohvdrat e s

103

3. Vitamins 4. I n s e c t i c i d e s and Insect Hormones 5. Antiinflammat o r y Agents

47

6. A n t i s e c r e t o r y Agents a.

b.

References are l i s t e d c h r o n o l o g i c a l l y by year. Chronological o r d e r i n g w i t h i n a given year was not attempted. While i t was intended t h a t a l l r e l e v a n t references i n the p e r i o d 1976-1978 should be i n c l u d e d i n t h i s t a b l e , there are undoubtedly many inadvertant omissions f o r which the author apologizes i n advance. A d d i t i o n a l references from t h i s p e r i o d are welcomed. E n t r i e s i n the t a b l e r e f e r t o the reference that describes the study that was c a r r i e d out.

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

COMPUTER-ASSISTED DRUG DESIGN

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Figure 1.

Morphine structure and atom numbering

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

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i n drug design. The techniques have evolved i n s e v e r a l other ways as w e l l . For example, e l e c t r o s t a t i c p o t e n t i a l maps have been found to be a q u i t e u s e f u l and s e n s i t i v e t o o l (Z5, 26_, 41, 44_, 46_, 57_, 71, 7_5, 99_) f o r i d e n t i f y i n g r e a c t i v i t y c h a r a c t e r i s t i c s of drugs, at l e a s t i n e l e c t r o p h i l i c r e a c t i o n s . Since these maps can be c a l c u l a t e d d i r e c t l y from the wavefunction, and are more s e n s i t i v e measures of the e l e c t r o n i c charge d i s t r i b u t i o n f o r chemical r e a c t i o n s than, e.g., the net charges and bond orders from a p o p u l a t i o n a n a l y s i s , t h e i r i n t r o d u c t i o n and use represent an important development i n the kinds o f t h e o r e t i c a l t o o l s a v a i l a b l e f o r use. In a d d i t i o n , the use o f s t a t i s t i c a l mechanics i n the i n t e r p r e t a t i o n o f conformational energies has f i n a l l y begun t o be considered (2S_ 79). A l s o , the use of pseudopotential theory, at l e a s t f o r cases when second-row atoms are i n v o l v e d , has been t r i e d i n s e v e r a l cases (43, 64, 83, 100), and shows good potential. Not only has the methodology developed s i g n i f i c a n t l y , but the models used t o represent b i o l o g i c a l events have improved s u b s t a n t i a l l y i n many cases. For example, not only have i s o l a t e d molecules been s t u d i e d , but models of the drug-receptor complex have been developed i n s e v e r a l cases (37_, 43_, 52, 56, 71, 77_, 81, 89, 90.5 97). In other cases, models f o r the t r a n s i t i o n s t a t e i t s e l f have been i n v e s t i g a t e d (6j0). In a d d i t i o n , solvent and other environmental e f f e c t s are i n c l u d e d more commonly than before (28_, 3J8, 39_, 40_, 49_ 5_5_, 79), even though i t i s recognized t h a t a f u l l y s a t i s f a c t o r y model o f solvent e f f e c t s that i s computationally f e a s i b l e i s not yet a v a i l a b l e . On the other hand, there are a v a r i e t y of. areas where subs t a n t i a l developmental e f f o r t s i n methodology and/or b i o l o g i c a l models are needed. Perhaps most s t r i k i n g i s the need f o r i n c l u s i o n of s u b s t a n t i a l l y l a r g e r numbers of geometric degrees of freedom when studying conformational c h a r a c t e r i s t i c s of molecules. While the study of the e n e r g e t i c dependence of one or two d i h e d r a l angle v a r i a t i o n s i s perhaps u s e f u l as a s t a r t i n g p o i n t , i t i s c l e a r that such s t u d i e s are l i m i t e d i n the conc l u s i o n s that can be e x t r a c t e d from them, and may i n some cases lead to incorrect conclusions. For example, even i n the case of " r i g i d " o p i a t e s , i t i s c l e a r that the f l e x i b i l i t y present i n the s t r a i n e d , m u l t i - r i n g s t r u c t u r e i s s i g n i f i c a n t and cannot be ignored. Even the C 1 2 - C 1 3 bond i n morphine (see Figure 1 ) , which forms the nexus of each of the f i v e r i n g s , can be shown t o allow a 30° v a r i a t i o n w i t h i n 3 kcal/mole or l e s s , using e i t h e r experimental or c a l c u l a t e d r e s u l t s (7^_). T h i s i s an important f l e x i b i l i t y t h a t should not be ignored f o r s e v e r a l reasons. F i r s t , changes i n t h i s angle w i l l change s u b s t a n t i a l l y the d i s t a n c e from the quaternary n i t r o g e n to the aromatic moiety (Ring A i n Figure 1 ) , which i s a f e a t u r e that i s thought by many to be important i n o p i a t e r e c e p t o r i n t e r a c t i o n s . Next, i f comparisons to other o p i a t e s 9

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In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

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are made and the molecular f l e x i b i l i t i e s of morphine and the comparison molecule are i g n o r e d , i t i s p o s s i b l e t o conclude that no s t r u c t u r a l s i m i l a r i t y e x i s t s when i n f a c t such s i m i l a r i t i e s do e x i s t . For example, when only two d i h e d r a l angle variations were c o n s i d e r e d ^ , 106), i t was concluded that meperidine and morphine could not be matched from a geometric p o i n t of view. On the other hand, i f a l l bond d i s t a n c e s , bond angles and dihed r a l angles are allowed t o r e l a x (74), a good f i t of the two molecules can be achieved at only modest e n e r g e t i c cost (-3.6 kcal/mole f o r the a x i a l form of meperidine, and 6.9 k c a l / mole f o r the e q u a t o r i a l form of meperidine). In a r e l a t e d i s s u e , the development of r e l i a b l e , f a s t , and g e n e r a l l y a p p l i c a b l e e m p i r i c a l p o t e n t i a l s (or other procedures) that w i l l allow examination o f l a r g e numbers of degrees o f freedom i n a wide v a r i e t y of c l a s s e s o f organic compounds remains an important unsolved problem. Just as i n the case o f neglect of geometric degrees o f freedom, the use of naive approximations or p o t e n t i a l f u n c t i o n s that omit obvious terms of importance cannot be expected t o provide r e l i a b l e r e s u l t s (78). More g e n e r a l l y , while there have been s u b s t a n t i a l c o n t r i b u t i o n s t o the development of e m p i r i c a l p o t e n t i a l s f o r s p e c i a l i z e d kinds of molecules, e.g., polypeptides (107), corresponding p o t e n t i a l s f o r the broad range of molecules that are t y p i c a l l y encountered i n drug design are not c u r r e n t l y a v a i l a b l e .

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New

Directions

In a d d i t i o n t o the developments already r e f e r r e d t o above, there are s e v e r a l other new d i r e c t i o n s that can be i d e n t i f i e d i n the recent l i t e r a t u r e , that i n d i c a t e the kinds o f a d d i t i o n a l advances that can be expected i n the next s e v e r a l years. As a f i r s t example i n t h i s r e g a r d , i t i s o f i n t e r e s t t o consider a study r e p o r t e d by E. Clementi and c o l l a b o r a t o r s (108) i n 1978. In t h i s paper, the manner of t r e a t i n g enzymic r e a c t i o n s using t h e o r e t i c a l techniques was g e n e r a l i z e d s u b s t a n t i a l l y from e a r l i e r work. Since the d e s c r i p t i o n of enzyme-substrate i n t e r a c t i o n s encounters the same kinds of d i f f i c u l t i e s as the desc r i p t i o n of drug-receptor i n t e r a c t i o n s , t h i s study may provide a good i n d i c a t i o n o f new d i r e c t i o n s and c a p a b i l i t i e s that can be expected t o develop f u r t h e r i n the near f u t u r e . In t h i s approach, enzymic r e a c t i o n s are considered t o be d i v i s i b l e i n t o two separate but r e l a t e d steps c a l l e d "macrodeformations" and "mierodeformations. Macrodeformations are intended to i n c l u d e the s t r u c t u r a l a l t e r a t i o n s that a f f e c t the e n t i r e enzyme p l u s s u b s t r a t e during the approach and r e a c t i o n of the substrate and departure o f the products. On the other hand, microdeformations recognize t h a t , a f t e r the o v e r a l l enzymesubstrate s t r u c t u r e i s approximately determined a f t e r approach of the s u b s t r a t e , a d e t a i l e d d e s c r i p t i o n of the chemical r e a c t i o n needs t o be considered. These c o n s i d e r a t i o n s assume that the ,f

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

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r e a c t i o n i s a r e l a t i v e l y " l o c a l i z e d " event, and that only a r e l a t i v e l y small number of moieties i n and around the a c t i v e s i t e plus the substrate need to be considered. Of course, the two processes cannot be r i g o r o u s l y separated as d e s c r i b e d , and a sequence of macrodeformations plus microdeformations i s used to model the various steps along the r e a c t i o n path. For the d e s c r i p t i o n o f the two kinds of processes, d i f f e r e n t kinds of t h e o r e t i c a l techniques were used. For macrodeformations, the primary processes that are assumed t o be o c c u r r i n g are a l a r g e number of non-bonded i n t e r a c t i o n s that l e a d to the i n t r o d u c t i o n of the substrate i n t o the a c t i v e s i t e (or departure of the products). For such processes, e m p i r i c a l p o t e n t i a l s are appropriate t o use f o r s e v e r a l reasons. First, e v a l u a t i o n of the t o t a l energy can be done r a p i d l y enough so that a l a r g e number of atoms and degrees of freedom can be examined. Next, as long as no bonds are made or broken, i t i s p o s s i b l e f o r e m p i r i c a l p o t e n t i a l s to provide a s a t i s f a c t o r y t h e o r e t i c a l framework. In the case of microdeformations, the a c t u a l chemical react i o n at the a c t i v e s i t e i s considered, and a d e t a i l e d ab i n i t i o quantum mechanical formulation i s used. For the i n i t i a l s t u d i e s described i n 1978, a minimum b a s i s set SCF c a l c u l a t i o n was c a r r i e d out, but the concept i s q u i t e general. As a f i r s t example, the c y s t e i n e p r o t e i n a s e , papain, was studied i n i t s c a t a l y t i c cleavage of peptide s u b s t r a t e s . The enzyme contains over 200 r e s i d u e s , and the p a r t i c u l a r mechanism that has been proposed by Drenth, et a l (109) was chosen f o r examination. In the macrodeformation steps, no l e s s than 73 residues plus substrate were considered, s t a r t i n g e s s e n t i a l l y from papain coordinates from X-ray s t u d i e s . In the main, the r e s u l t s of macrodeformation s t u d i e s o f substrate entry are s t r u c t u r e s that are r e l a x e d e n e r g e t i c a l l y from the X-ray c r y s t a l coordinates, i n c l u d i n g the formation of s e v e r a l new hydrogen bonds and the movement of s e v e r a l atoms i n the a c t i v e s i t e i n a manner that w i l l f a c i l i t a t e the subsequent enzyme-substrate r e a c t i o n . In the mierodeformation s t u d i e s , low energy s t r u c t u r e s f o r various intermediates were sought, i n c l u d i n g the form of the a t t a c k i n g species and the s t r u c t u r e of the t e t r a h e d r a l intermediate. It i s not expected that e i t h e r the s t r u c t u r e "refinements" of the enzyme or substrate that occurred during macrodeformation steps or the e n e r g e t i c or s t r u c t u r a l features found as a r e s u l t of mierodeformation steps are r e l i a b l e enough at t h i s stage t o provide conclusive new i n s i g h t i n t o the enzymatic behavior of papain. However, these s t u d i e s i n d i c a t e c l e a r l y that the " s t a t e o f - t h e - a r t " has now changed s u b s t a n t i a l l y , and that meaningful models of enzyme-substrate or drug-receptor i n t e r a c t i o n s can now be examined using t h e o r e t i c a l techniques. Another example that i l l u s t r a t e s new d i r e c t i o n s of i n t e r e s t r e l a t e s t o the experimental c h a r a c t e r i z a t i o n at the molecular

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

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l e v e l o f drug-receptor complexes. S p e c i f i c a l l y , the X-ray s t u d i e s of S o b e l l and c o l l a b o r a t o r s (110-11?) on the b i n d i n g o f drugs t o DNA models provide a good example o f the l e v e l o f d e t a i l i n d e s c r i b i n g drug-receptor i n t e r a c t i o n s t h a t i s now p o s s i b l e experimentally . The p a r t i c u l a r system t h a t was s t u d i e d i n v o l v e d the b i n d i n g of ethidium, a known DNA i n t e r c a l a t o r , t o two d i f f e r e n t model DNA s t r u c t u r e s [ 5 - i o d o u r i d y l y l ( 3 - 5 ) a d e n o s i n e and 5 - i o d o c y t i d y l y l ( 3 - 5 ) guanosine], followed by c r y s t a l l i z a t i o n of the complexes and a c q u i s i t i o n p l u s a n a l y s i s o f s u f f i c i e n t X-ray data t o allow atomic r e s o l u t i o n ( i . e . , standard d e v i a t i o n s of +0.1A f o r bond lengths and ±5° f o r bond a n g l e s ) . The DNA-drug models used embody a l a r g e number o f the f e a t u r e s known t o be important, i . e . , double stranded DNA " m i n i - h e l i x e s " are formed, with ethidium i n t e r c a l a t e d between two p a i r s o f hydrogen bonded bases that are connected by the u s u a l sugar-phosphate backbone. These s t u d i e s give r i s e t o a v a r i e t y o f important s t r u c t u r a l f e a t u r e s o f such complexes, as w e l l as t o provide s e v e r a l mechanistic hypotheses t h a t can be i n v e s t i g a t e d f u r t h e r u s i n g t h e o r e t i c a l techniques. For example, these s t u d i e s suggest t h a t drug i n t e r c a l a t i o n r e s u l t s i n a h e l i c a l screw d i s l o c a t i o n i n the DNA double h e l i x , whose magnitude determines the r e l a t i v e r i n g overlap between an i n t e r c a l a t e d drug molecule and adjacent base p a i r s . A l s o , conformational changes i n the sugar-phosphate backbone accompany drug i n t e r c a l a t i o n , which l e d t o the suggestion that DNA " k i n k s " f i r s t , followed by i n t e r c a l a t i o n o f the drug. Such observations and suggestions, while very important c o n t r i b u t i o n s , a l s o r a i s e a s e r i e s o f questions which need f u r t h e r study, and f o r which t h e o r e t i c a l techniques are now a v a i l a b l e . Thus, both t h e o r e t i c a l and experimental s t u d i e s i n d i c a t e t h a t s i g n i f i c a n t new d i r e c t i o n s can be expected i n the next s e v e r a l years t h a t w i l l enhance s u b s t a n t i a l l y the a b i l i t y t o c a r r y out drug design u s i n g techniques h e r e t o f o r e not a v a i l a b l e . Furthermore, c u r r e n t and l i k e l y developments i n both hardware and software f o r minicomputers w i l l extend even f u r t h e r the o p p o r t u n i t i e s f o r use o f s o p h i s t i c a t e d t h e o r e t i c a l techniques on problems i n drug design. !

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Acknowledgement s The author would l i k e t o express h i s deep a p p r e c i a t i o n t o the Upjohn Company f o r t h e i r c o n t i n u i n g support o f t h i s r e s e a r c h , and t o Drs. E.C. Olson, B.V. Cheney, D. Duchamp and many others at the Upjohn Company f o r t h e i r e x c e l l e n t comments and c o l l a b o r a t i o n over many years. In a d d i t i o n , support f o r t h i s symposium and t o t h i s author from the H a r r i s Corporation i s g r a t e f u l l y acknowledged.

In Computer-Assisted Drug Design; Olson, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

1. CHRISTOFFERSEN

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RECEIVED

June

8, 1979.

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