Rational design of novel compounds to serve as potential NDM-1 inhibitors using molecular docking, molecular dynamics simulation, and physicochemical studies

Abstract

Abstract New Delhi Metallo-β-lactamase enzyme (NDM-1) is an enzyme that hydrolyzes a wide range of β-lactam antibiotics, including most carbapenems, leading to antimicrobial resistance. The development of a novel NDM-1 inhibitor for use in combination with carbapenems may help to combat drug-resistant pathogens. Twenty compounds derived from naphthalene, thiazole, and sulfone derivatives were designed to inhibit bacterial NDM-1 and protect β-lactam antibiotics from enzyme attack. Two- and three-dimensional structures of the designed molecules were sketched using MarvinSketch, and a molecular docking protocol was used to identify potential inhibitor(s) of the NDM-1 target protein using AMDock v 1.5.2. The binding free energy of each compound against NDM-1 was determined and the drug-likeness properties of the designed molecules were assessed using SwissADME. Two compounds with the highest ΔGbinding results, T008 and T016, were selected for further investigation using molecular dynamic (MD) simulations with the GROMACS simulation package (GROMACS 2020.4). The duration of each MD simulation was 100 ns. Both compounds had a significantly higher binding free energy than the positive control and other designed molecules, their MD simulations remained stable, they passed Lipinski’s rule of five, and were shown to have favorable physicochemical properties. The study outcomes can be used to inform synthesis and in vitro testing of the selected molecules.