Ligand Shaping in Induced Fit Docking of MraY Inhibitors. Polynomial Discriminant and Laplacian Operator as Biological Activity Descriptors.

Claudiu N Lungu,Mircea V Diudea,Mihai V Putz

doi:10.3390/ijms18071377

Abstract

Docking—i.e., interaction of a small molecule (ligand) with a proteic structure (receptor)—represents the ground of drug action mechanism of the vast majority of bioactive chemicals. Ligand and receptor accommodate their geometry and energy, within this interaction, in the benefit of receptor–ligand complex. In an induced fit docking, the structure of ligand is most susceptible to changes in topology and energy, comparative to the receptor. These changes can be described by manifold hypersurfaces, in terms of polynomial discriminant and Laplacian operator. Such topological surfaces were represented for each MraY (phospho-MurNAc-pentapeptide translocase) inhibitor, studied before and after docking with MraY. Binding affinities of all ligands were calculated by this procedure. For each ligand, Laplacian and polynomial discriminant were correlated with the ligand minimum inhibitory concentration (MIC) retrieved from literature. It was observed that MIC is correlated with Laplacian and polynomial discriminant.

Highlights

Such topological surfaces were represented for each MraY inhibitor, studied before and after docking with MraY
Phospho-MurNAC-pentapetide translocase (MraY) is an enzyme involved in bacterial cell wall biosynthesis
Because the goal of this study is to develop a methodology to predict the bioactivity based on the ligand structure, the receptor (MarY) was considered rigid in simulating the molecular recognition process

Summary

Introduction

Phospho-MurNAC-pentapetide translocase (MraY) is an enzyme involved in bacterial cell wall biosynthesis. Mray is the target for five families of nucleosides which are natural antibacterials: the tunicamycins, liposydomycins, muraymycins, and capuraymicins [2]. These compounds act as inhibitors of MraY. This enzyme is regarded as an ideal target for novel antibiotics due to its crucial role in generating the cellular envelope and because it lacks in mammalian cells. A computational method of determining the bioactivity of five MraY inhibitors is presented This method is based on descriptors that relate to molecular recognition process. Because the goal of this study is to develop a methodology to predict the bioactivity based on the ligand structure, the receptor (MarY) was considered rigid in simulating the molecular recognition process.

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Conclusion