Structure-based virtual screening of essential Mycobacterium tuberculosis enzymes AspS and KatG for potential inhibitors.

Andrew P Collins

doi:10.6026/97320630017101

Abstract

Mycobacterium tuberculosis (TB) is a leading global cause of disease-related death. Recent works have studied metabolic pathways of the mycobacterium, highlighting essential enzymes to target via competitive inhibition through computational molecular modeling to suppress the organism's life cycle. We used the Protein Databank (PDB), the UniProt Knowledgebase and the iDock server in this study. In vitro toxicity screening and pharmacokinetic properties were assessed to determine potential ligand safety and drug properties. Our results have revealed five and nine potential ligands for the enzymes AspS and KatG respectively. The KatG active site has displayed binding affinities of -13.443 to -12.895 kcal/mol, while AspS ligands range from -6.580 to -6.490kcal/mol. The intermolecular forces responsible for the differing binding affinities of each enzyme are primarily Coulombic interactions for AspS, versus Coulombic and extensive hydrogen bonding interactions in KatG.

Highlights

Mycobacterium tuberculosis is estimated to infect nearly one quarter of the world’s population, roughly 1.7 billion people
International Union of Pure and Applied Chemistry (IUPAC) molecule names are listed for identification as well
The aminoacyl tRNA synthetase ribosomal protein biosynthesis serves as an essential enzyme in the metabolic function and life cycle of Mycobacterium tuberculosis

Summary

Introduction

Mycobacterium tuberculosis is estimated to infect nearly one quarter of the world’s population, roughly 1.7 billion people. The disease is latent in most cases, over 10 million patients are infected with the active disease each year, with an overall mortality rate as high as 12.3% [1,2]. The prevalence of varying degrees of drugresistant strains is increasing, making disease containment a clinical challenge [3]. Many of those infected today do not have access to the antibiotic protocols or are infected with multi-drug resistant strains that are not manageable through current pharmaceuticals. The discovery of drugs depended on trial

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