Comparative modeling and dynamic simulation of UDP-N-acetylmuramoyl-alanine ligase (MurC) from Mycobacterium tuberculosis through virtual screening and toxicity analysis

Abstract

IntroductionUDP-N-acetylmuramic-alanine ligase (MurC) is an enzyme catalyzing the addition of L-alanine to UDP-acetylmuramoyl nucleotide precursor in Mycobacterium tuberculosis (M. tuberculosis). This enzyme is a prerequisite for the biosynthesis of the peptidoglycans in M. tuberculosis. AimThis study aimed to identify the novel inhibitors of MurC using in silico approach. Materials and MethodsThe three dimensional (3D) structure of MurC was determined using comparative modeling and based on the template obtained from Haemophilus influenza (1P31). The structural analysis of the model structure shown that three residues (Lys126, Glu170, and Glu358) are critical for in the catalytic activity of the enzyme, and their inhibition will block the function of the enzyme. Ten thousand and ninety-five (10095) compounds obtained through virtual screening against Zinc and PubChem databases based on their ability to bind to MurC with minimum binding energies. These ligands screened for the physicochemical properties, molecular docking, and pharmacokinetic analyses. FindingSix compounds had desirable physicochemical and pharmacokinetic properties with excellent binding energy ranged between −12.27 and −10.09 kcal/mol. These compounds subjected to Molecular Dynamic (MD) Simulation and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analyses. The outcome of the analysis revealed that four ligands (PubChem1548994, ZINC11882115, ZINC22241774, and ZINC12330603) formed a stable conformation in the substrate-binding site of the protein during the 50 ns MD simulation. ConclusionTherefore, the ligands mentioned above might regard as novel inhibitors of M. tuberculosis which requires further in vitro and in vivo validation.