Docking, Scoring, and Virtual Screening in Drug Discovery

Abstract

Since its introduction about four decades ago, docking and scoring are now the very heart of structure‐based drug design. The past 10–20 years have seen a plethora of docking and scoring tools successfully integrated into drug discovery pipelines. Interestingly, while artificial intelligence is now receiving significant attention in the computational modeling arena, docking and scoring have long utilized these techniques. This comprehensive summary highlights some of the most significant achievements of docking and scoring, reviews the current status, provides descriptions of many of the tools available, comments on some of the outstanding challenges facing the paradigm, and offers perspectives and advice on best practices for users. While significant development is still needed in docking of flexible molecules and accurate Gibb's free energy predictions, docking and scoring are very useful when handled by experienced practitioners, but less so if treated as a “black box.” Lastly, we present a hypothetical case so beginners may appreciate the nuances of setting up a docking study. Focus in docking is now shifting toward parallel applications, i.e. protein–protein, protein–oligosaccharide, protein–DNA, or protein–RNA docking and polypharmacology. In summary, this article is intended to elucidate the nuances of the subject, while providing guidelines for practical implementation of effective workflows in drug discovery and structural biology.

β-Lactamase Suppression as a Strategy to Target Methicillin-Resistant Staphylococcus aureus: Proof of Concept

“…It would be interesting to model the interactions of GraS with 1 , 2 , and 3 , but a BLAST search clearly demonstrated that no appropriate templates are available: the closest structure was WalK from Bacillus subtilis , but it had <30% sequence identity to the GraS kinase domain, albeit it was higher in the ATP-binding pocket. The complexity 30 of modeling interactions of chemicals with homology models coupled with the absence of experimental confirmation of interaction with GraS and P2As makes it impractical to include those results in this manuscript.…”