CVC Seminar: Wed Apr 20 1:30-3pm ACES 4.304

Maysam Moussalem

Lead Optimization in Computational Drug Design: An Iterative Approach to Structural and Chemical Refinement

In lead optimization, a target-drug complex returned as the result of a docking experiment must then go through simultaneous chemical optimization and structural refinement, with the goal of improving the complex’s binding affinity as well as its pharmacokinetic properties (absorption, distribution, metabolism, elimination, toxicity — ADMET properties), making it a stronger candidate for subsequent stages of the drug development process. Due to the very large set of parameters which need to be explored, lead optimization is often described as the tightest bottleneck in the drug discovery process.

In this talk, we briefly summarize prior work in lead optimization and then go on to propose (1) an iterative algorithm for solving this multi-parameter optimization problem of simultaneous chemical modification and structural refinement, (2) a reduced flexibility model for the efficient modeling of large proteins’ relevant degrees of freedom, and (3) an improved and “tunable” scoring function.