Can we use docking and scoring for hit-to-lead optimization?

Abstract

Docking and scoring is currently one of the tools used for hit finding and hit-to-lead optimization when structural information about the target is known. Docking scores have been found useful for optimizing ligand binding to reproduce experimentally observed binding modes. The question is, can docking and scoring be used reliably for hit-to-lead optimization? To illustrate the challenges of scoring for hit-to-lead optimization, the relationship of docking scores with experimentally determined IC₅₀ values measured in-house were tested. The influences of the particular target, crystal structure, and the precision of the scoring function on the ability to differentiate between actives and inactives were analyzed by calculating the area under the curve of receiver operator characteristic curves for docking scores. It was found that for the test sets considered, MW and sometimes ClogP were as useful as GlideScores and no significant difference was observed between SP and XP scores for differentiating between actives and inactives. Interpretation by an expert is still required to successfully utilize docking and scoring in hit-to-lead optimization.