Multipose Binding in Molecular Docking

Sergey Samsonov,Kalina Atkovska,M. Pisabarro,Maciej Paszkowski-Rogacz

doi:10.3390/ijms15022622

Abstract

Molecular docking has been extensively applied in virtual screening of small molecule libraries for lead identification and optimization. A necessary prerequisite for successful differentiation between active and non-active ligands is the accurate prediction of their binding affinities in the complex by use of docking scoring functions. However, many studies have shown rather poor correlations between docking scores and experimental binding affinities. Our work aimed to improve this correlation by implementing a multipose binding concept in the docking scoring scheme. Multipose binding, i.e., the property of certain protein-ligand complexes to exhibit different ligand binding modes, has been shown to occur in nature for a variety of molecules. We conducted a high-throughput docking study and implemented multipose binding in the scoring procedure by considering multiple docking solutions in binding affinity prediction. In general, improvement of the agreement between docking scores and experimental data was observed, and this was most pronounced in complexes with large and flexible ligands and high binding affinities. Further developments of the selection criteria for docking solutions for each individual complex are still necessary for a general utilization of the multipose binding concept for accurate binding affinity prediction by molecular docking.

Highlights

Continuous developments in technology and structural and functional genomics result in the discovery of many new proteins that can represent potential drug targets
The corresponding binding poses were further studied by applying an molecular dynamics (MD) approach and Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA)
Molecular docking has been shown to be a useful tool in virtual screening of small molecules binding to proteins

Summary

Introduction

Continuous developments in technology and structural and functional genomics result in the discovery of many new proteins that can represent potential drug targets. This raises the necessity for new and fast computational approaches alternative to wet-lab high-throughput screens for drug discovery [1,2,3]. One of the most commonly used computational screening methods is molecular docking, which aims to predict the structure and binding affinity of a complex between a receptor and a ligand [3,4,5]. A recent study of seven commonly used docking programs applied to

Objectives

Methods

Results

Conclusion