Fragment-based tailoring of compound libraries for high-throughput docking and screening

COMP 81

Peter Kolb, kolb@blur.compbio.ucsf.edu1, Catherine Berset Kipouros2, Danzhi Huang3, Fabian Dey3, and Amedeo Caflisch3. (1) Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158, (2) Oncalis AG, Wagistr. 21, 8952 Schlieren, Switzerland, (3) Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland
High-throughput docking is a computational tool frequently used to discover small-molecule inhibitors of enzymes or receptors of known three-dimensional structure. However, the large number of molecules in chemical databases make automatic procedures for pruning libraries before docking useful. We propose Anchor-based Library TAiloring (ALTA) as a strategy to focus chemical libraries by docking and prioritizing molecular fragments according to their binding energy. ALTA is able to identify compounds with optimal anchor fragments without any knowledge of known inhibitors.

We applied ALTA to the EphB4 receptor tyrosine kinase and docked 21418 molecules of a tailored library (obtained from an initial collection of about 730000), followed by ranking according to force-field-based energy including electrostatic solvation. Among 43 compounds tested in vitro, eight molecules originating from two different anchors show low-micromolar activity in a fluorescence-based enzymatic assay. Four of them are active in a cell-based assay and are potential anti-angiogenic compounds.

 

Computational Approaches for Fragment Screening
8:00 AM-11:30 AM, Monday, August 18, 2008 Sofitel -- Orleans, Oral

Division of Computers in Chemistry

The 236th ACS National Meeting, Philadelphia, PA, August 17-21, 2008