Structure-based drug design: Combinatorial chemistry and molecular modeling

Drug discovery efforts are shifting to include the rapid synthetic procedur es of combinatorial chemistry and the elegance of rational library design. The wealth of computational methods which explore both the receptor structu re and the ultimate pharmacophore complementarity, provide novel avenues fo r chemists to discover new lead compounds or design virtual libraries for s creening prior to the synthetic stage. This mini-review provides an overvie w of a few current methodologies of library generation, highlighting dockin g procedures which have utility in both the discovery and optimization stag es of drug development. Three specific examples of different approaches to the use of docking are provided. These describe the development of inhibito rs to the human A(3) adenosine receptor and HIV-1 protease, and the evaluat ion of the activity of novel inhibitors of the redox regulator protein, hum an thioredoxin.