Computational identification of natural inhibitors targeting GroEL in Leptospira interrogans: an integrative virtual screening and molecular dynamics approach

Introduction: and represents a major public health and veterinary concern. The persistence of the pathogen is closely associated with biofilm formation, yet targeted therapeutics are currently unavailable. The GroEL chaperonin, a conserved protein involved in biofilm formation and immunogenicity, was investigated as a potential therapeutic target. Methods: A structure-based virtual screening approach was performed using a library of 543,503 natural compounds from the Life Chemicals database. Top-ranked ligands were evaluated using molecular docking and physicochemical and pharmacokinetic property analyses. Density functional theory calculations were performed to assess electronic stability, followed by molecular dynamics simulations to evaluate ligand-protein complex stability. Principal component analysis and MM-PBSA binding free energy calculations were subsequently applied to characterize conformational dynamics and binding affinity. Results: Five compounds (F3385-2019, F1243-0200, F3139-0927, F2801-0179, and F1864-0208) exhibited strong binding affinities toward GroEL, with docking energies ranging from -10.34 to -8.26 kcal/mol. All shortlisted compounds complied with Lipinski's Rule of Five and demonstrated favorable pharmacokinetic properties. Molecular dynamics simulations and MM-PBSA analyses indicated stable ligand-protein interactions. Among the candidates, F1864-0208 and F1243-0200 emerged as the most stable and promising leads, whereas the remaining compounds showed moderate inhibition. Discussion: studies are required to validate their therapeutic efficacy and safety.