In silico screening and molecular dynamics analysis of natural DHPS enzyme inhibitors targeting Acinetobacter baumannii

Over time, antimicrobial agents are losing their credibility in curbing infections due to the development of resistant pathogen strains. The resistant strains have proven to invade living beings and cause various diseases, leading to deaths at an alarming rate. Acinetobacter baumannii is one such pathogen, and to target it through enzyme inhibition, Dihydropteroate synthase enzyme's active site is virtually screened for antimicrobial agents against in-house libraries of natural molecules from medicinally important plants and Agaricus spp. fungus. Two ligands (MSID_000725 and CID_291096) are found to be suitable candidate inhibitors after various screening through Lipinski's based drug-like parameters, pharmacokinetic parameters, toxicity parameters and structural parameters which comprised of estimated free energy of binding, ligand efficiency and interaction analysis. DHPS enzyme catalyses the condensation reaction of hydroxymethyl-7, 8-dihydropterin pyrophosphate and para-aminobenzoic acid in the folic acid synthesis pathway in bacterial cells. The Complexes of the DHPS enzyme and ligands are validated through in silico studies, including MD simulations and MM/PBSA based binding free energy studies. The Complex DHPS-MSID_000725 and DHPS-CID_291096 were analysed for global dynamics attributes such as RMSD, RMSF, Rg, SASA and essential dynamics through PCA. The complexes were subjected to MM/PBSA based binding free energy analysis and were found to have binding free energy of -25.18 kcal/mol (DHPS-MSID_000725) and - 4.90 kcal/mol (DHPS-CID_291096).