Ursolic acid as a potential inhibitor of mycobacterium tuberculosis cytochrome bc1 oxidase: a molecular modelling perspective.
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Date
2021
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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.
Description
Masters Degree. University of KwaZulu-Natal, Durban.