Introduction

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health concern, further complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains that reduce the effectiveness of conventional therapies. ClpC1, a protease regulatory ATPase essential for Mtb survival, has emerged as a promising therapeutic target. Natural products such as cyclomarin A and ecumicin inhibit ClpC1 effectively, but their complex structures and poor pharmacokinetics restrict clinical application. Calophyllum inophyllum, a tropical plant with documented antimicrobial activity, may serve as a source of novel ClpC1 inhibitors.

Methods

In this study, 52 phytoconstituents from C. inophyllum were screened using in silico approaches including molecular docking, ADMET profiling, PAINS filtering, and biological activity prediction.

Results

Friedelin and Canophyllal showed strong binding affinity (−7.8 and −7.7 kcal/mol) toward ClpC1, superior to the control inhibitor HEPES (−3.7 kcal/mol), forming stable interactions with key residues. ADMET evaluation indicated favorable pharmacokinetics, high gastrointestinal absorption, and no toxicity alerts. Molecular dynamics simulations up to 500 ns confirmed stability, with both compounds exhibiting lower RMSD and RMSF values than free ClpC1. Principal component and free energy landscape analyses validate their stability.

Conclusion

Outcomes of the study highlighted Friedelin and Canophyllal as promising scaffolds for developing ClpC1-targeting anti-TB agents, meriting further experimental validation.