Identification of novel p38 MAP kinase inhibitors using new Glide docking and scoring algorithms


Thomas A. Halgren1, Leah L. Frye2, Jeremy R. Greenwood1, Robert B. Murphy2, and Richard A. Friesner3. (1) Schrodinger, Inc, 120 W 45th Street, New York, NY 10036, (2) Schrödinger, 1500 SW First Ave., Suite 1180, Portland, OR 97201, (3) Department of Chemistry, Columbia University, 3000 Broadway, MC 3110, New York, NY 10027
Economic pressures have intensified efforts to decrease the time needed to bring a new drug to market and to reduce the cost, and computational methods are increasingly relied upon to expedite lead discovery. We have recently made fundamental advances in sampling and scoring algorithms for virtual screening that have led to greater accuracy in identifying active ligands. In particular, improved docking accuracy has enabled us to develop an advanced scoring function ("extra precision" mode, XP) for Glide (J. Med. Chem. 2004, 47, 1739-1749; 1750-1759) that effectively rejects "false positives" by significantly penalizing physically inappropriate interactions and that more efficiently identifies compounds likely to bind strongly by rewarding key binding motifs. The increased enrichment allows a smaller number of docked ligands to be submitted to further detailed analysis, including assessment of induced fit, ligand strain energy and visualization. Using our hierarchical protocol we docked a database of 500,000 available compounds, prefiltered for drug-like ADME properties with QikProp, to a p38 MAP kinase receptor conformation believed to favor selectivity. Of 1000 top-scoring compounds, post-processing produced a shortlist of 70 for purchase and screening as kinase inhibitors. Of 28 compounds screened to date, 8 compounds representing novel chemotypes exhibited better than 50% inhibition and may be suitable as lead candidates. Four compounds have been analyzed further and gave IC50 values ranging between 1.8 and 9.8 µM; IC50 determinations are pending for the remaining 4 hits, but we believe that one or two of these may be submicromolar. This study demonstrates that our computational algorithms and our virtual screening methodology are mature enough to present a viable alternative to High Throughput Screening at greatly reduced cost where sufficient target structural information is available.

Docking and Scoring
9:00 AM-12:20 PM, Sunday, August 22, 2004 Pennsylvania Convention Center -- 109B, Oral

Division of Computers in Chemistry

The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004