DFT and Molecular Dynamics Simulation Studies of 4-(2-(2-(2- Chloroacetamido)phenoxy)acetamido)-3-Nitrobenzoic Acid and 4-(2- (Benzo[D]thiazol-2-ylthio)acetamido)-3-Nitrobenzoic Acid against Escherichia coli ParE Enzyme

Abstract

Background: The increased emergence of multidrug-resistant bacterial strains is a continuous life-threatening global problem. The best approach to prevent the reproduction and invasion of the pathogenic bacteria is to inhibit the replication stage. The untapped molecular machinery involved in the replication is ParE subunit of topoisomerase IV. In this study, compounds active against the ParE were selected. Objective: This study aimed to analyze the electronic parameters, chemical stability, kinetic stability, and binding modes of the compounds. Methods: Density functional theory (DFT) and molecular electrostatic potential (MESP) calculations were computed using Jaguar with a basis set of 6-31G**++ (B3LYP) in the gas phase. MD simulation was performed for the 100 ns using Desmond available in Maestro to determine the stability and obtain an insight into the molecular mechanism of E. coli ParE docked complexes. Results: From the DFT calculations, the energy gap ΔE -7.58 and -7.75 eV between the HOMO and LUMO of both the compounds P1 (4-(2-(2-(2-chloroacetamido)phenoxy)acetamido)-3-nitrobenzoic acid) and P2 (4-(2-(benzo[d]thiazol-2-ylthio)acetamido)-3-nitrobenzoic acid) explained the chemical and kinetic stability of the system. MD results demonstrated the minimum fluctuations and conformational stability of the protein structures. Conclusion: The P1 and P2 compounds were chemically and kinetically stable. Furthermore, MD results demonstrated the stability and inhibitory action of the ligands dependent on hydrophobic, ionic and water bridges than that of hydrogen-bonding interactions.