Structural and functional characterization of 1-deoxy-D-xylulose-5-phosphate synthase (DXS) from : identification of promising lead molecules from virtual screening, molecular docking and molecular dynamics simulations.

The advent of multi drug resistance and extensive-drug resistance among various pathogens has caused a rise in nosocomial infections, which in turn has led to rising hospital-acquired infection-related mortality rates. Amongst them, carbapenem-resistant is one of the most notorious bacterial species, categorized as a Priority 1: Critical pathogen by the WHO. Therefore, the discovery and development of novel antibiotics, as well as the identification of potential inhibitors, have become the need of the hour. In this study, we have employed computational methods to explore and identify molecules capable of inhibiting enzymes essential in the methylerythritol 4-phosphate (MEP) biosynthetic pathway. The high throughput virtual screening of small molecules (Enamine Advanced Collection (AC) library) against the highly conserved substrate-binding site of the DXS target protein provided us with a total of 1000 molecules. The top four potential candidate molecules, namely-Z3353989070, Z3353989049, Z2295848528, and Z1685501455, alongside fluoropyruvate (control), a known inhibitor of DXS, was chosen for a molecular dynamic simulation study. The molecular dynamic simulation trajectories suggested high structural and thermodynamical stability and strong binding affinity of all the DXS-ligand complexes. Moreover, the MM/PBSA-based binding free energy calculations also exhibited strong interactions of the selected ligand molecules with DXS. In conclusion, we have found that all four molecules displayed better results and stronger binding affinity than the control. In the end, based on all the above-mentioned criteria, we have proposed Z3353989049 to be the promising lead candidate against DXS from .Communicated by Ramaswamy H. Sarma.