Computational Chemistry

Chapter 1, Harder Questions, Answers

Q8

Consider the docking of a potential drug molecule X into the active site of an
enzyme: a factor influencing how well X will “hold” is clearly the shape of X; can
you think of another factor?
Hint: molecules consist of nuclei and electrons.
Another factor which comes to mind is charge. The shape factor arises from
what could be called steric complementarity: ideally, for each bulge on X there is a
corresponding depression on the active site, and vice versa. Another kind of
complementarity arises from electrical charge: for each positive/negative region
on X there is negative/positive region (ideally of complementary shape). So for
strong binding we would like each positively charged bulge on X to fit into a
negatively charged depression, ideally of he same shape and size, in the active site,
and analogously for positively charged depressions and negatively charged bulges.
Of course this situation is unlikely to be always exactly realized.
The hint was to remind us that in most molecules there is a substantial imbalance
between positive and negative charge from place to place in the molecule.

Chapter 1, Harder Questions, Answers

Q9

In recent years the technique ofcombinatorial chemistryhas been used to quickly
synthesize a variety of related compounds which are then tested for pharmacologi-
cal activity (Borman S (2001) Chemical and Engineering News, 27 August, p 49;
2000, 15 May, p 53; 1999, 8 March, p 33). What are the advantages and disadvan-
tages of this method of finding drug candidates, compared with the “rational
design” method of studying, with the aid of computational chemistry, how a
molecule interacts with an enzyme?

COOH

I

COOH

I

COOH

I

COOH

I

COOH

I

COOH

I

COOH

I

COOH

I

COOH

I

COOMe

I

COOMe

I

COOMe

I

COOEt

I

COOEt

I

COOEt

I

COOPr

I

COOPr

I

COOPr

I

COOMe

F

COOEt

F

COOPr

F

COOMe

Cl

COOEt

Cl

Cl

COOPr

COOMe

Br

Br

COOEt

Br

COOPr

All nine cells the same Three different compounds Nine different compounds

592 Answers