Rapid Shape-Based Ligand Alignment and Virtual Screening Method Based on Atom/Feature-Pair Similarities and Volume Overlap Scoring

Abstract

Shape-based methods for aligning and scoring ligands have proven to be valuable in the field of computer-aided drug design. Here, we describe a new shape-based flexible ligand superposition and virtual screening method, Phase Shape, which is shown to rapidly produce accurate 3D ligand alignments and efficiently enrich actives in virtual screening. We describe the methodology, which is based on the principle of atom distribution triplets to rapidly define trial alignments, followed by refinement of top alignments to maximize the volume overlap. The method can be run in a shape-only mode or it can include atom types or pharmacophore feature encoding, the latter consistently producing the best results for database screening. We apply Phase Shape to flexibly align molecules that bind to the same target and show that the method consistently produces correct alignments when compared with crystal structures. We then illustrate the effectiveness of the method for identifying active compounds in virtual screening of eleven diverse targets. Multiple parameters are explored, including atom typing, query structure conformation, and the database conformer generation protocol. We show that Phase Shape performs well in database screening calculations when compared with other shape-based methods using a common set of actives and decoys from the literature.

Discovery of Novel Second Mitochondria-Derived Activator of Caspase Mimetics as Selective Inhibitor of Apoptosis Protein Inhibitors

“…We used the phase shape program in Canvas to run the virtual screening. It initiates finding trial alignments based on the principle of the distribution of atom triplets and then refines the top alignments to maximize the volume overlap (Sastry et al, 2011). The hits with high structure similarity to the AVPI template then were further screened through the docking study.…”

High throughput virtual screening based discovery of dengue protease inhibitor

“…The logic in contrasting shape properties is that it takes into consideration molecules having shape similarity by rapid flexible superimposition of several similar molecules so that they can fit well and bind to the active pocket of protein or enzyme more efficiently. 21 Formation of non-covalent bonds between oppositely charged moieties is enabled by force involving electrostatic interactions. Relationship between polarity of the ligand and its relative biological activity is examined by electrostatic parameter.…”

Fragment-based Shape Signatures: a new tool for virtual screening and drug discovery

“…Phase Shape screening was performed using the program Phase [57, 58]. Descriptors were generated applying the pure volume scoring (“Shape Sim Pure”) and compared to 1D Shape Signatures.…”