Pocket to concavity: a tool for the refinement of protein–ligand binding site shape from alpha spheres

Abstract

Summary Understanding the binding site of the target protein is essential for rational drug design. Pocket detection software predicts the ligand binding site of the target protein; however, the predicted protein pockets are often excessively estimated in comparison with the actual volume of the bound ligands. This study proposes a refinement tool for the pockets predicted by an alpha sphere-based approach, Pocket to Concavity (P2C). P2C is divided into two modes: Ligand-Free (LF) and Ligand-Bound (LB) modes. The LF mode provides the shape of the deep and druggable concavity where the core scaffold can bind. The LB mode searches the deep concavity around the bound ligand. Thus, P2C is useful for identifying and designing desirable compounds in Structure-Based Drug Design (SBDD). Availability and implementation Pocket to Concavity is freely available at https://github.com/genki-kudo/Pocket-to-Concavity. This tool is implemented in Python3 and Fpocket2. Supplementary information Supplementary data are available at Bioinformatics online.

Site Identification and Next Choice Protocol for Hit-to-Lead Optimization

“…In the first step of the SINCHO protocol, the growth sites where the lead functional groups can be placed were identified. P2C was used for the first step . P2C accurately searches for deep concavities in the target protein based on the default pockets obtained from sphere-based pocket detection software.…”

“…P2C was used for the first step. 35 P2C accurately searches for deep concavities in the target protein based on the default pockets obtained from sphere-based pocket detection software. The ligand-bound (LB) mode in P2C provides growth sites around the hit compound.…”

“…Our protocol comprises three steps: site identification, anchor atom selection, and next choice. For site identification, the growth site, where the lead substructure can be placed around the hit compound, was searched using the Pocket to Concavity (P2C) tool, as proposed in our previous study . For each detected growth site, the starting atom for modification with functional groups was specified based on the geometrical criteria between the heavy atom of the hit compound and the growth site for anchor atom selection.…”

“…For site identification, the growth site, where the lead substructure can be placed around the hit compound, was searched using the Pocket to Concavity (P2C) tool, as proposed in our previous study. 35 For each detected growth site, the starting atom for modification with functional groups was specified based on the geometrical criteria between the heavy atom of the hit compound and the growth site for anchor atom selection. In the final step, desirable pairs between the anchor atom and growth site were selected based on the scoring function.…”