Library design based on privileged structures through docking and direct design in the protein binding pocket

COMP 185

Christof Gerlach1, Hans FG Velec2, Michael Smolinski3, David G. Hangauer, hangauer@acsu.buffalo.edu3, Andreas Heine2, and Gerhard Klebe2. (1) Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, 35032, Germany, (2) Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Germany, Marbacher Weg 6, Marburg, Germany, (3) Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260
Successful automated computational ligand design requires rigorous validation of predicted binding geometries. Assessing the predictive power of our inhibitor design tools we selected trypsin and thrombin as well-established model cases. Via the analysis of ligand binding using ITC we factorize binding affinity into thermodynamic contributions. We start with a privileged ligand scaffold well-suited to address key interactions of the recognition pattern shared by serine proteases. Binding modes of these privileged scaffolds are generated by docking. The best ranked solutions are optimized by local searches based on knowledge-based potentials derived from CSD. For individual members of the series the crystal structure and the binding-affinity towards both enzymes are determined. Facing experimental data with the computer-generated geometries assesses the predictive power of the latter. Starting with the determined binding geometry of the privileged scaffold and searches by docking routines for novel side-chain decorations reveals ligands with optimal complementarity to the target protein.

Poster Session -- Sponsored by Novartis Institutes for BioMedical Research
6:00 PM-8:00 PM, Tuesday, 30 August 2005 Washington DC Convention Center -- Hall A, Poster

8:00 PM-10:00 PM, Monday, 29 August 2005 Washington DC Convention Center -- Hall A, Sci-Mix

Division of Computers in Chemistry

The 230th ACS National Meeting, in Washington, DC, Aug 28-Sept 1, 2005