The most important aspect of computer-assisted modeling is the capability to
perform three-dimensional docking experiments, a tool used by all major drug companies
and biotechnology firms. Starting with the X-ray structure of the macromolecule, a space-
filling molecular model is created, including hydrate envelopes around it. By separately
generating the three-dimensional model of a hypothetical drug, a modeler can manipu-
late the two by modern fast computers and can directly examine the fit of the ligand in
the active site; the investigator can change the substituents, conformation, and rotamers
of the drug on the screen, and can repeat the docking.
This enormous progress in computer hardware and software, elucidation of macro-
molecular structure and ligand–receptor interactions, crystallography, and molecular
modeling is hopefully bringing us to the threshold of a breakthrough in drug design. We
are now able to design lead compounds de novo on the basis of the structure of the recep-
tor macromolecule. However, computerized drug design is still only an instrument that
reduces empiricism in an experimental science; the inherent approximations of innu-
merable conformers and molecular parameters of drug and receptor, and the method-
ological inaccuracies and difficulties of comparison, will never allow the elimination of
insight and trial.
3.2.6 Lead Compound Identification by Combinatorial
Chemistry with High Throughput ScreeningRandom screening,while seemingly wasteful, has an important place in developing
lead compounds in areas in which theory lags. Screening for antitumor activity has been
carried on for more than 30 years by the U.S. National Cancer Institute, with tens of
thousands of compounds being tested on tumors in vivoandin vitro. More recently, a
computerized prescreening method has been applied to this process, saving time and
expense, and hence the screening is not as random as it used to be. A successful random
search for antibacterial action was conducted by several pharmaceutical companies in
the 1950s. They tested soil samples from all over the world, which resulted in the dis-
covery of many novel structures and some spectacularly useful groups of antibiotics,
notably the tetracyclines (3.4). In fact, microbial sources have supplied an enormous
number of new drug prototypes, sometimes of staggering complexity. Recently, the
large-scale automated testing of microbial mutants has been realized and combined
with recombinant DNA techniques to speed up the efficient discovery and production
of new antibiotics.
Some would argue that drug discovery through screening provides the “irrational”
counterpart to rational drug design. This remark is unjustifiably harsh and is somewhat
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 121