Geometric filters for protein–ligand complexes based on phenomenological molecular models

O O Sudakov,M O Platonov,D B Kovalskyy,O M Balinskyi

doi:10.7124/bc.000833

O O Sudakov, M O Platonov + Show 2 more

Open Access

https://doi.org/10.7124/bc.000833

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Abstract

Molecular docking is a widely used method of computer-aided drug design capable of accurate prediction of protein-ligand complex conformations. However, scoring functions used to estimate free energy of binding still lack accuracy. Aim. Development of computationally simple and rapid algorithms for ranking ligands based on dockingresults.Methods.Computationalfiltersutilizinggeometryofprotein-ligandcomplexweredesigned.Efficiency of the filters was verified in a cross-docking study with QXP/Flo software using crystal structures of human serine proteases thrombin (F2) and factor Xa (F10) and two corresponding sets of known selective inhibitors.Results. EvaluationoffilteringresultsintermsofROCcurveswithvaryingfilterthresholdvaluehasshown their efficiency. However, none of the filters outperformed QXP/Flo built-in scoring function Pi . Nevertheless, usage of the filters with optimized set of thresholds in combination with Pi achieved significant improvement in performance of ligand selection when compared to usage of Pi alone. Conclusions. The proposed geometric filters can be used as a complementary to traditional scoring functions in order to optimize ligand search performance and decrease usage of computational and human resources.

Highlights

IntroductionComputer-aided drug design is a widely used technique
Nowadays, computer-aided drug design is a widely used technique
Docking is the procedure of protein and small molecule complexes geometry optimization aimed at finding the global energy minimum of the system

Summary

Introduction

Computer-aided drug design is a widely used technique. It is mostly based on molecular docking and scoring approach [1]. Docking is the procedure of protein (target) and small molecule (ligand) complexes geometry optimization aimed at finding the global energy minimum of the system. The most likely configuration of the complex corresponds to the Gibbs free energy minimum. Energy is usually estimated using certain force field model and its minimization is performed by various methods. A large collection of small molecules is docked against the protein active site. Different characteristics (scores) are calculated to estimate binding free energy. Ligands with the highest scores are filtered for further

Methods

Results

Conclusion