Antituberculosis potential of borrelidin derivatives: An in silico molecular docking and molecular dynamic approach

Abstract

Background: The present tuberculosis (TB) treatment requires a significant time commitment, often lasting from 6 months to 2 years, with strict daily adherence. Non-compliance leads to drug resistance and suboptimal outcomes. Present research indicates that borrelidin shows potential activity against Mycobacterium tuberculosis, including strains that are resistant to first-line medications. Borrelidin has shown remarkable activity against M. tuberculosis H37Rv, with a minimum inhibitory concentration value of 3.12 µg/mL. Therefore, investigating the inhibition activity of borrelidin derivatives was essential for finding new anti-TB candidates. Objectives: This study aims to investigate the effects of 31 borrelidin derivative compounds on M. tuberculosis proteins. Methods: Molecular docking studies were performed on 31 borrelidin compound designs to predict their activity against M. tuberculosis proteins. This was followed by molecular dynamics studies, molecular mechanics-general born-surface area (MM-GBSA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties predictions. This method can yield the best activity predictions. Results: The docking result revealed that the 31 borrelidin derivatives had binding energies in a range of −8.90–−10.43 kcaL/moL. These binding energies were higher than rifampin as the native ligand (−13.10 kcaL/moL). However, this is lower than isoniazid (−4.90 kcaL/moL), pyrazinamide (−4.70 kcaL/moL), and moxifloxacin (−7.80 kcaL/moL) as control positives, which is remarkable. During a 100 ns simulation time, borrelidin R7, R15, R17, and R29 are more stable compared to rifampin as the native ligand. Binding energy calculations using the MM-GBSA method showed that compound R17 has the lowest binding energy. Compound R17 also fulfills ADMET properties, as well as parameters related to ADMET tests. Conclusion: Although borrelidin R17 has limitations due to its unsuitability for transport through the renal organic cation transporter 2 and its inability to act as a substrate for P-glycoprotein (P-gp) or as an inhibitor of P-gp II, based on these findings, borrelidin R17 appears to be the most promising candidate for further evaluation as a new anti-TB agent.