Exploration of potential hit compounds targeting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) from Acinetobacter baumannii: an in silico investigation.

The emergence of carbapenem-resistant Acinetobacter baumannii, a highly concerning bacterial species designated as a Priority 1: Critical pathogen by the WHO, has become a formidable global threat. In this study, we utilised computational methods to explore the potent molecules capable of inhibiting the IspC enzyme, which plays a crucial role in the methylerythritol 4-phosphate (MEP) biosynthetic pathway. Employing high-throughput virtual screening of small molecules from the Enamine library, we focused on the highly conserved substrate binding site of the DXR target protein, resulting in the identification of 1000 potential compounds. Among these compounds, we selected the top two candidates (Z2615855584 and Z2206320703) based on Lipinski's rule of Five and ADMET filters, along with FR900098, a known IspC inhibitor, and DXP, the substrate of IspC, for molecular dynamics (MD) simulations. The MD simulation trajectories revealed remarkable structural and thermodynamic stability, as well as strong binding affinity, for all the IspC-ligand complexes. Furthermore, binding free energy calculations based on MM/PBSA (Molecular Mechanics/Poisson-Boltzmann Surface Area) methodology demonstrated significant interactions between the selected ligand molecules and IspC. Taking into consideration all the aforementioned criteria, we suggest Z2206320703 as the potent lead candidate against IspC. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03923-w.

Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii - A computational study.

A. baumannii is a ubiquitously found gram-negative, multi-drug resistant bacterial species from the ESKAPE family of pathogens known to be the causative agent for hospital-acquired infections such as pneumonia, meningitis, endocarditis, septicaemia and urinary tract infections. A. baumannii is implicated as a contributor to bloodstream infections in approximately 2% of all worldwide infections. Hence, exploring novel therapeutic agents against the bacterium is essential. LpxA or UDP-N-acetylglucosamine acetyltransferase is an essential enzyme important in Lipid A biosynthesis which catalyses the reversible transfer of an acetyl group on the glucosamine 3-OH of the UDP-GlcNAc which is a crucial step in the biosynthesis of the protective Lipopolysaccharides (LPS) layer of the bacteria which upon disruption can lead to the elimination of the bacterium which delineates LpxA as an appreciable drug target from A. baumannii. The present study performs high throughput virtual screening of LpxA against the enamine-HTSC-large-molecule library and performs toxicity and ADME screening to identify the three promising lead molecules subjected to molecular dynamics simulations. Global and essential dynamics analysis of LpxA and its complexes along with FEL and MM/PBSA based binding free energy delineate Z367461724 and Z219244584 as potential inhibitors against LpxA from A. baumannii.