Ursolic acid as a potential inhibitor of mycobacterium tuberculosis cytochrome bc1 oxidase: a molecular modelling perspective.

Abstract

Tuberculosis (TB) is a disease, caused by an infectious agent; Mycobacterium tuberculosis, which persists as a major problem globally, especially in developing countries such as Brazil, Indonesia, and South Africa. Individuals who are diabetic and human immunodeficiency virus (HIV) co-infected are at a higher risk of contracting TB. Hence, these risk factors are associated with a compromised immune system. Among these factors, various strains are involved in the pathogenesis of TB such as multidrug-resistant tuberculosis (MDR-TB) and extensively drugresistant tuberculosis (XDR-TB) strains. The emergence of these strains may result from failure to complete treatment within the stipulated period of six months. However, studies show that the protein QcrB; contributes more to TB pathogenesis. Therefore, there is an urgent need for the discovery of drugs that inhibit QcrB. The current FDA-approved anti-tubercular drugs such as, Lansoprazole sulfide (LSPZ) and Telacebec (Q203) which inhibit QcrB are bacteriostatic and have been linked to side effects including dementia, chronic kidney disease, and ischemic cardiac diseases [1], thus prompting a search for an alternative drug. Various natural compounds have been reported to possess several bioactivities that could be crucial in the management of tuberculosis (TB) disease. Warbugia salutaris, a medicinal plant has been found to exhibit inhibitory properties against M. tuberculosis. Numerous compounds are derived from W. salutaris. In this study, we focus solely on Ursolic acid (UA) and its derivative, Ursolic acid acetate (UAA). These two compounds possess antibacterial, anti-HIV, and antimycobacterial properties. This suggests that they could potentially possess inhibitory properties towards M.tuberculosis QcrB protein. In this study, computational methods are applied to investigate the inhibitory activity of UA and UAA on M. tuberculosis QcrB. Molecular Docking, Molecular Dynamics (MD) simulations, Radius of Gyration, Principal Component Analysis (PCA), and Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) binding free energy calculations were performed in explicit solvent to accomplish our goal. The obtained results indicated that the (1) the binding of UA to QcrB induced a more stable and compacted conformation compared to LSPZ and Q203; (2) high total binding free energy estimated in the QcrB-UA system was due to numerous hydrophobic residues in the binding site of QcrB that interact with phenyl rings of UA resulting in hydrophobic packing. This implies that UA has a high binding affinity and, as a result, a strong inhibition of QcrB; (3) more H-bonds were observed in the QcrB-UA system than in the QcrBQ203 system; (4) rigidity was displayed mostly in Arg124 and Thr128; (5) Arg124 and Phe127 also contributed more to the total binding energy in QcrB-UA and QcrB-UAA. This implies that the ligands exert a high binding affinity in the porphyrin binding site than in the active site. The identification of a molecule that competes with the porphyrin ring for the binding site could be beneficial in QcrB pharmacological research; (6) UA could be a potential anti-tubercular agent through QcrB inhibition, although it is hepatotoxic within tolerable concentrations. However, observed potential hepatotoxicity was based on predictions. Although the preliminary findings of this report warrant further experimental validation, they lay a strong foundation for subsequent assessment and development of these natural compounds as antitubercular drugs.