About Authors: Aswini K. Reddy, Swetha Yasa, Srivally Challa, Masoom. md
Mallareddy Institute of Pharmaceutical Sciences, Hyderabad
ABSTRACT
Both solid- and liquid-phase combinatorial chemistry have emerged as powerful tools for identifying pharmacologically active compounds and optimizing the biological activity of a lead compound. Complementary high-throughput in vitro assays are essential for compound evaluation. Cell-based assays that use optical endpoints permit investigation of a wide variety of functional properties of these compounds including specific intracellular biochemical pathways, protein-protein interactions, and the subcellular localization of targets. Integration of combinatorial chemistry with contemporary pharmacology now represents an important factor in drug discovery and development.
This is an exceptionally exciting time in the field of pharmacology. The environment for the identification of new therapeutic targets and agents that interact with these targets has rapidly changed with the application of genetic tools and genomics. Extrapolation from the genomic sequencing of lower organisms suggests that there will be a 10-fold increase in the number of potential human therapeutic targets in the next several years with the completion of the Human Genome Project (Drews, 1996). This is leading to a fundamental transformation in pharmacology; no longer is there a dearth of molecular targets for small molecules. Rather, the emphasis is now on validating whether or not the targets are appropriate for therapeutic intervention, on generating large arrays of compounds that represent diverse portions of “chemical space”, and developing methods to quickly assess the credentials of small molecules as target disrupters. We believe many of the tools and reagents that are being developed to facilitate this scientific activity will emerge as vital for future academic pharmacological research. Perhaps most important will be the exploitation of combinatorial chemistry libraries, which are becoming widely available. Although we cannot comprehensively review this broad topic here, the goal of this brief commentary is to portray some of the strategies and potentials of combinatorial chemistry libraries as they relate to pharmacological studies.