Computational Repurposing and Phytochemical Screening of Inhibitors Against ClpK from Klebsiella pneumoniae.

Over the years, the increase in antibiotic resistant Klebsiella pneumoniae has highlighted the urgent need for the identification of novel therapeutic compounds and targets. ClpK is a caseinolytic ATPase that plays an important role in protein quality control and thermotolerance, making it a promising drug target. This study used in silico methods including ADMET screening, molecular docking and molecular dynamics simulations to evaluate binding efficiency and dynamic stability of selected natural and synthetic compounds with ClpK under varying ionic conditions. ADMET screening of synthetic and natural compounds excluded compounds violating Lipinskis rule of 5 or showing predicted toxicity. Sclerotiamide P was identified as the top binder (-10.9 kcal/mol), while compound D3 had the weakest binding (-4.5 kcal/mol). The top ten compounds with the most favourable binding scores were then further investigated using molecular dynamics simulations in the presence of NaCl and MgCl2. Trajectory and MM-GBSA binding analyses confirmed that ClpK-ligand complexes remained stable in both ionic environments, with negative binding free energy values indicative of favourable interactions. Overall, the study highlighted ADEP3 and sclerotiamide derivatives as promising ClpK inhibitors and provides a foundation for further experimental validation.