STRUCTURE BASED DESIGN: INHIBITOR OF HIV RT

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The Kuntz group activities primariliy involve structure-based ligand design methods. We are interested in extracting structural information with advanced algorithms; computer graphics routines to display structures; refinement procedures; interactive energy minimization with state-of-the-art potential functions; drug design tools such as DOCK and COMBIDOCK. We have begun a program to couple organic synthesis (DIVERSIFY) with computational searching. DIVERSIFY, uses organic transformations to generate a large family of products from specified starting points. The reagents and/or resulting compounds can then be screening using our DOCK technology. The DOCK software package for searching data bases of organic compounds for putative ligands has been a central aspect of UCSF drug design efforts. This suite of programs has wide-ranging applications to enzyme systems, nucleic acids, and, in general, problems involving molecular recognition.The curren version of the program uses the AMBER intermolecular potential functions to evaluate proposed binding geometries. DOCK was developed to propose novel lead compounds. It has been successful in this goal in a wide variety of systems, including recent, unpublished work identifying novel inhibitors of the HIV reverse transcriptase. Progress has also been made on the software front. Combinatorial library design for inhibitors of cathepsin D in collaboration with the Ellman laboratory at UC Berkeley has been published and a first step at a graphical user interface has been prepared.