Brian Shoichet, Ph.D.
Professor of Pharmaceutical Chemistry

Contact Information:
shoichet@cgl.ucsf.edu
Tel: (415) 514-4126
Fax: (415) 502-1411
Box 2550, MB, QB3,
Room 5 North 508D

Links:
Lab Website

Publications:
Complete
Selected

Structure-based Inhibitor Discovery, Computer modeling and experimental testing, enzyme structure, function, and stability

We are interested in how enzyme structure determines function, with a focus on novel inhibitor discovery. A major emphasis is the inhibition and evolution of ß-lactamase. The research combines computational modeling with enzymology, protein stability, and x-ray crystallography.

1. Development and testing of docking methods. Molecular docking fits ligands into receptor structures, and is widely used for drug discovery. The problem is challenging because of the many possible ways of putting two molecules together and the difficulties of calculating energies in condensed phases. We thus emphasize detailed testing of new algorithms in well-controlled experimental systems. Two model systems are used: ß-lactamase and a cavity site in lysozyme.

2. A general mechanism for non-specific inhibition of enzymes by small molecules. An unanticipated consequence of working with model systems was the discovery of a general mechanism for non-specific inhibition. This is a huge problem in drug discovery and it appears to have a simple biophysical mechanism: promiscuous "inhibitors" aggregate into large particles in solution, and these particles can inhibit just about anything. We are investigating how these aggregates interact with enzymes, and the range of compounds that can act this way.

3. ß-lactamases as targets for inhibitor discovery. ß-lactamases are the primary resistance mechanism to the pencillin-class of antibiotics. Using a structure-based approach, we seek to discover novel inhibitors of these enzymes. A question with which we are now grappling is can we develop a single inhibitor that will be active against WT and mutant resistance enzymes, or will we need to tailor different inhibitors to different mutants?

4. Stability & activity constraints on enzyme evolution. Over 100 mutant ß-lactamases, resistant to ever more penicillin analogs, have been isolated in the last 20 years in the clinic. We have found that as ß-lactamases evolve to become active against larger and larger penicillins, their active sites enlarge and they give up intrinsic stability. This suggests that there may be fundamental biophysical constraints on their evolution or evolutionary pathway. These constraints may be used in the design of new inhibitors.

Selected Publications:
Wei BQ, Baase WA, Weaver LH, Matthews BW, Shoichet BK. A model binding site for testing scoring functions in molecular docking. Journal of Molecular Biology 322, 339-355 (2002).

McGovern SL, Caselli E, Grigorieff N, Shoichet BK. A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. Journal of Medicinal Chemistry 45, 1712-1722 (2002).

Powers RA, Morandi F, Shoichet BK. Structure-based discovery of a novel, non-covalent inhibitor of AmpC ß-lactamase. Structure 10, 1013-1023 (2002).

Wang X, Minasov G, Shoichet BK. Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs. Journal of Molecular Biology 320, 85-95.