The broad aim of this work is to understand the molecular forces that determine the interaction of proteins with ligands. The goal is the development of the theory needed for molecular design. This project focuses on computer-assisted design of ligands for macromolecular receptors of known structure using a program called DOCK. The current DOCK program creates negative images of receptor surfaces and positive images of ligands. It then explores in a systematic way the six degrees of freedom involved in fitting together two rigid bodies. It 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 ligand design. In the coming grant period we suggest ways to make very substantial improvements in the performance and speed of the DOCK program, and we suggest direct approaches to the de novo design and optimization of active ligands. The specific proposals for DOCK modifications are: to develop conformational searching for ligand and receptor; to introduce more quantitative scoring by accounting for solvation effects and differential scoring; and to speed up the search process through shape cluster analysis and code improvements. For the ligand design section, we propose to: automate ligand modification procedures; continue development of a de novo ligand construction program called BUILDER; explore """"""""positive"""""""" imaging for mimetic design; incorporate pharmacological properties into our databases. The DOCK approach to ligand discovery and design has had some important initial successes in the development of novel lead compounds as inhibitors of the HIV protease; the interruption of the CD4-gp 120 recognition event that precedes HIV infection; and inhibition of influenza virus, among others. DOCK is an important tool in structure-based design and has helped to speed up the drug discovery process.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031497-15
Application #
2444542
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1983-03-01
Project End
1998-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
15
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kang, Xinshan; Shafer, Richard H; Kuntz, Irwin D (2004) Calculation of ligand-nucleic acid binding free energies with the generalized-born model in DOCK. Biopolymers 73:192-204
Fujii, Naoaki; Haresco, Jose J; Novak, Kathleen A P et al. (2003) A selective irreversible inhibitor targeting a PDZ protein interaction domain. J Am Chem Soc 125:12074-5
Greenbaum, Doron C; Arnold, William D; Lu, Felice et al. (2002) Small molecule affinity fingerprinting. A tool for enzyme family subclassification, target identification, and inhibitor design. Chem Biol 9:1085-94
Huo, Shuanghong; Wang, Junmei; Cieplak, Piotr et al. (2002) Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions: insight into structure-based ligand design. J Med Chem 45:1412-9
Laboissiere, Martha C A; Young, Malin M; Pinho, Rilva G et al. (2002) Computer-assisted mutagenesis of ecotin to engineer its secondary binding site for urokinase inhibition. J Biol Chem 277:26623-31
Pegg, S C; Haresco, J J; Kuntz, I D (2001) A genetic algorithm for structure-based de novo design. J Comput Aided Mol Des 15:911-33
Aronov, A M; Munagala, N R; Kuntz, I D et al. (2001) Virtual screening of combinatorial libraries across a gene family: in search of inhibitors of Giardia lamblia guanine phosphoribosyltransferase. Antimicrob Agents Chemother 45:2571-6
Ewing, T J; Makino, S; Skillman, A G et al. (2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des 15:411-28
Lamb, M L; Burdick, K W; Toba, S et al. (2001) Design, docking, and evaluation of multiple libraries against multiple targets. Proteins 42:296-318
Sullivan, D C; Kuntz, I D (2001) Conformation spaces of proteins. Proteins 42:495-511

Showing the most recent 10 out of 56 publications