The broad aim of this work is to understand the molecular forces that determine the interaction of proteins with ligands. Our immediate goal is the development of the theory needed for molecular design, especially on the discovery and optimization of pharmaceutically interesting ligands. This proposal describes computer-assisted design of ligands for macromolecular receptors of known structure using a program called DOCK. The current DOCK program (version 4.0) creates negative images of receptors surfaces and positive images of ligands. It then explores in a systematic way rigid docking. The new version now implements several methods of """"""""flexible"""""""" docking in which the conformation of the ligand is varied automatically during the docking process. The program does this operation rapidly enough that we can use large structural databases- the Cambridge Structural Database, the Fine Chemicals Directory, and the Chemical Abstracts Registry- as a source of molecular templates for ligan design. In the coming grant period we suggest ways to make substantial improvements in the performance and speed of the DOCK program, and we describe a new effort to use structure-based methods to design combinatorial chemistry libraries. Preliminary experimental results, in collaboration with Prof. Jon Ellman at UC Berkeley, are very encouraging. The specific proposals for DOCK modifications are: to develop conformational searching for the receptor; to introduce evaluation of free energy of binding for a diverse set of ligands; to speed up the search process through new site descriptors and code improvements; and to develop a WEB-based user interface. For the combinatorial library design section, we propose to develop methods to explore virtual libraries of 109-1010 organic compounds; to automate scaffold evaluation and selection; to set up clustering, docking and scoring routines for large libraries; and to explore the incorporation of desirable pharmacological properties in an early stage of library design. We also describe some new ideas for testing the new algorithms. The DOCK approach to ligand discovery and design has led to the discovery of novel lead compounds as inhibitors of the HIV protease, HIV reverse transcriptase, and the influenza virus, among others. DOCK is an important tool in structure-based design and has helped to speed up the drug discovery process.
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