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Structure-Based Drug Design

Irwin D. Kuntz¹, Conrad C. Huang², and Thomas E. Ferrin²

¹ Department of Pharmaceutical Chemistry
University of California, San Francisco

² Computer Graphics Laboratory
University of California, San Francisco

This project is aimed at combining a number of computationally-based approaches into a system to help design new ligands and drugs. The figure below depicts this integrated approach to structure-based drug design. Key among these tools is the DOCK software package developed by the Kuntz group at USCF to propose novel lead compounds. This system has been used successfully in a wide variety of systems (see references below). The DOCK suite of programs focuses on molecular recognition, with wide-ranging applications to enzyme systems, protein-protein interfaces, nucleic acids, and protein-nucleic acid complexes. The current version of the program (DOCK 4.01) uses full AMBER intermolecular potential functions and flexible ligand minimization to evaluate proposed binding geometries. New methods being incorporated into DOCK include free energy-based scoring functions and receptor flexibility. Finally, considerable emphasis has been placed on the design of combinatorial libraries, coupled to successful experiments on inhibitor development.

Interactive graphics continues to be a critical tool to identify regions of interest in a receptor site. By using the CombiBuild and CombiDOCK programs, users can automatically join molecules together from a library of chemically acceptable linkages. As depicted in the figure above, the entire process can be viewed directly using a Chimera extension, ViewDock.


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