Identification of multikinase inhibitor using a multistep computer aided approach

MEDI 366

Sivanesan Dakshanamurthy, sd233@georgetown.edu1, Mikell Paige2, Todd Hansen2, Salimuddin Shah2, Stephen Byers2, and Milton Brown2. (1) oncology, Lombardi Cancer Center, Georgetown University, reservoir road, E401/W225, NRB, washington, DC 20057, (2) oncology, Georgetown University, washington, DC 20057
In recent years, computer based virtual screening has become a powerful tool for the drug discovery. However, major challenge in the Computer Aided Drug Design (CADD) is obtaining accurate protein-ligand binding affinity because conventional scoring functions fails to include protein flexibility, solvation penalty, and conformational entropy. In some cases, the binding modes that correspond to the largest calculated binding free energy are not necessarily the actual binding modes found in the crystallographic complexes. Thus, free energy simulations are good alternative to rescore the binding complexes. In this study, we formulated a multi-step CADD approach in which each step acts as a filter that employs step by step filters to identify only the most promising candidates. We successfully applied this multi-step approach to the identification of multi-kinase inhibitors.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007