Importance of consensus region of multiple-ligand templates in a virtual screening method

Abstract

We discuss methods and ideas of virtual screening (VS) for drug discovery by examining the performance of VS-APPLE, a recently developed VS method, which extensively utilizes the tendency of single binding pockets to bind diversely different ligands, i.e. promiscuity of binding pockets. In VS-APPLE, multiple ligands bound to a pocket are spatially arranged by maximizing structural overlap of the protein while keeping their relative position and orientation with respect to the pocket surface, which are then combined into a multiple-ligand template for screening test compounds. To greatly reduce the computational cost, comparison of test compound structures are made only with limited regions of the multiple-ligand template. Even when we use the narrow regions with most densely populated atoms for the comparison, VSAPPLE outperforms other conventional VS methods in terms of Area Under the Curve (AUC) measure. This region with densely populated atoms corresponds to the consensus region among multiple ligands. It is typically observed that expansion of the sampled region including more atoms improves screening efficiency. However, for some target proteins, considering only a small consensus region is enough for the effective screening of test compounds. These results suggest that the performance test of VS methods sheds light on the mechanisms of protein-ligand interactions, and elucidation of the protein-ligand interactions should further help improvement of VS methods.

Local Interaction Density (LID), a Fast and Efficient Tool to Prioritize Docking Poses

“…Different ways of incorporating structural information have been proposed, for example by introducing spatial constraints targeting parts of the ligand that are common with a reference ligand, by guiding the placement of the ligand on reference atom-centered functions or electron density, or by scoring pose by 3D pharmacophore matching similarity [27,28,29]. Okuno et al suggested to combine multiple ligand-protein crystallographic structure into a reference grid [30,31]. The method, called VS-APPLE, aligned the ligand with the reference grid to predict the binding mode.…”

A prospective compound screening contest identified broader inhibitors for Sirtuin 1

“…In the process of seeking inhibitors of the target protein, an LBSV method, VS-APPLE 53,54 , was used. While conventional ligand-based VS methods adopt single ligand as a template, VS-APPLE adopts the multiple-ligand template, which is composed of multiple ligands bound to the same pocket, as a template.…”

Preface of Special Issue “Protein-Ligand Interactions”

“…Okuno et al . [ 10 ] discussed a new virtual screening method for drug discovery, especially in the case that a number of different ligands bind to a protein pocket. Even in the era of high performance computing, they warned that detailed understanding of the mechanisms of protein-ligand interactions is the prerequisite for the improvement of the screening.…”