Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors.

ABSTRACT: Hit-to-lead virtual screening frequently relies on a cascade of computational methods that starts with rapid calculations applied to a large number of compounds and ends with more expensive computations restricted to a subset of compounds that passed initial filters. This work focuses on set up protocols for alchemical free energy (AFE) scoring in the context of a Docking-MM/PBSA-AFE cascade. A dataset of 15 congeneric inhibitors of the ACK1 protein was used to evaluate the performance of AFE set up protocols that varied in the steps taken to prepare input files (using previously docked and best scored poses, manual selection of poses, manual placement of binding site water molecules). The main finding is that use of knowledge derived from X-ray structures to model binding modes, together

SUBMITTER: Granadino-Roldan JM 

PROVIDER: S-EPMC6413950 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature