Identification of novel zinc-binding inhibitors against key microbial metallohydrolase DapE in Klebsiella pneumoniae: an integrated ligand-based virtual screening, molecular docking, molecular dynamics, and MM/PBSA approach

Klebsiella pneumoniae (K. pneumoniae) has emerged as a prominent multidrug-resistant pathogen in healthcare settings and is ranked among the top three critical priority pathogens by the World Health Organization. Owing to the surge in antibiotic resistance and resulting treatment failures, there is an urgent need for alternative therapeutic approaches. N-succinyl-L, L-diaminopimelic acid desuccinylase (DapE), a crucial metalloenzyme in the lysine biosynthesis pathway in K. pneumoniae, is essential for protein synthesis and the cross-linking of the bacterial peptidoglycan cell wall. The remarkable conservation of DapE across diverse bacterial species makes it a promising target for combating drug resistance. In this study, 400 analogues were screened using virtual screening to evaluate their pharmacokinetic, toxicological, and bioactive properties. Fifty-two compounds meeting these criteria were selected for molecular docking analysis. Among these, five top-ranking compounds were identified based on docking scores, and two, ZINC262925003 (-7.1 kcal/mol) and ZINC237355153 (-7.0 kcal/mol), were selected due to their strong catalytic zinc-binding interactions at the active site. Extensive validation through 250 ns molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) analysis revealed high structural stability and robust binding interactions for these complexes. These findings highlight their potential as therapeutic agents against DapE, necessitating further validation through in vitro and in vivo studies. Insight Box The study employs an integrated computational approach for identifying potential zinc-binding inhibitors against Klebsiella pneumoniae's DapE (KpDapE). In recent times, antimicrobial resistance has become a global challenge in treating bacterial infections. DapE, a metalloenzyme in the lysine biosynthesis pathway in K. pneumoniae, is essential for protein synthesis and the cross-linking of the bacterial peptidoglycan cell wall. DapE is a promising drug target to develop a new class of drugs. In this study, 400 L-Captopril analogues were screened, identifying two candidates as potent leads. Molecular docking and dynamics simulations revealed that ZINC262925003 and ZINC237355153 had significant binding affinity and stable interactions with KpDapE, supported by RMSD, RMSF, and binding-free energy analyses. This suggests that both these compounds could be potent inhibitors for KpDapE.