Virtual screening of protein receptor targets has become a standard approach in the pharmaceutical industry for small molecule drug discovery projects.  However, the hit rate for challenging targets (which are often the most interesting) is frequently in the low single digits.  We will describe the performance of the latest version of the Wscore docking methodology, in combination with absolute binding free energy (ABFEP) calculations, which is capable of increasing hit rates into the 10-30% range even for difficult systems.  Wscore incorporates explicit waters into its docking protocol, as well as identification of a wide range of key molecular recognition motifs, achieving superior performance for docking accuracy, determination of the principle sources of binding affinity for a wide range of ligands and receptors, and assessment of desolvation effects.  The top scoring compounds obtained from Wscore screening are then evaluated via ABFEP, the results of which display a strong correlation with experimental binding data.  We will outline the methodology of both approaches, and then discuss both retrospective calculations using public data sets, and prospective results obtained from recent drug discovery projects.

Improved accuracy in virtual screening via Wscore docking and absolute binding free energy calculations

ACS Spring 2022

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