High throughput docking for library design and library prioritization

TLDR

Prioritizing combinatorial library screening is crucial for rapidly identifying tight‑binding ligands and pharmaceutical compounds, and when target structures are available, molecular docking can be used for this prioritization. We present an initial validation of a rapid molecular docking approach designed to prioritize combinatorial libraries. The algorithm was tested on 103 protein‑data‑bank cases, correctly docking ligands within 2.0 Å of the observed binding mode in nearly 90 % of them. With a mean CPU time of less than 5 s per molecule, the method can process hundreds of thousands of compounds per week, and a faster, less thorough search reduces this to 1 s per molecule, enabling millions of compounds to be docked weekly. Proteins 2001;43:113‑124.

Abstract

The prioritization of the screening of combinatorial libraries is an extremely important task for the rapid identification of tight binding ligands and ultimately pharmaceutical compounds. When structural information for the target is available, molecular docking is an approach that can be used for prioritization. Here, we present the initial validation of a new rapid approach to molecular docking developed for prioritizing combinatorial libraries. The algorithm is tested on 103 individual cases from the protein data bank and in nearly 90% of these cases docks the ligand to within 2.0 A of the observed binding mode. Because the mean CPU time is <5 s/mol, this approach can process hundreds of thousands of compounds per week. Furthermore, if a somewhat less thorough search is performed, the search time drops to 1 s/mol, thus allowing millions of compounds to be docked per week and tested for potential activity. Proteins 2001;43:113-124.