If a reliable bioassay is available, it is possible to screen thousands or even millions
of compounds against this bioassay. The crystal structures of key protein receptors do
not have to be known; indeed, the proteins do not even have to be identified. If the
bioassay is fast and efficient, and if the library of compounds being screened is diverse
and comprehensive, then in principle it should be possible to identify a lead compound
years before the practitioner of rational drug design. However, the key to success lies in
the “goodness of the library of compounds” (i.e., a combinatorial chemistry library) and
in the “goodness of the screening bioassay” (i.e., high throughput screening methods).
3.2.6.3 Combinatorial Chemistry and Drug Discovery by Screening
A key to success in drug discovery by screening is the availability of a large and struc-
turally diverse library of compounds. If the library contains a million compounds that
are all analogs of each other, then it may be large but it is probably not sufficiently
diverse. The library should have the full range of functional groups (cations, anions,
hydrogen bond donors, hydrogen bond acceptors, lipophilic, aromatic, etc.) displayed
in all possible permutations and combinations in three-dimensional space. Creating
such a library is not a trivial task.
Combinatorial chemistryis both the philosophical and the practical method with
which to create structurally diverse compound libraries. Combinatorial chemistry is
defined as that branch of synthetic organic chemistry that enables the concomitant syn-
thesis of large numbers of chemical variants in such a manner as to permit their evalu-
ation, isolation, and identification. Combinatorial chemistry affords techniques for the
systematic creation of large but structurally diverse libraries. From a technical perspec-
tive, there are several avenues of approach to library creation:
- Libraries of oligomers of naturally occurring monomers
a. Oligopeptide libraries
b. Oligonucleotide libraries - Libraries of oligomers of non-naturally occurring monomers
a. Oligocarbamate libraries
b. Oligourea libraries
c. Oligosulfone libraries
d. Oligosulfoxide libraries - Libraries of monomers with multiple sites for substituents
a. Synthetic ease privileged structure
Dioxapiperazines
b. Pharmacological activity privileged structures
Benzodiazepines
Dihydropyridines
Hydantoins
c. Novel template structures
Dihydrobenzopyrans
Historically, the first major libraries were oligomers of naturally occurring monomers.
A good example would be a library of all possible tripeptides. Using the twenty naturally
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 123