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Tuberculosis (TB), the most frequent bacterium-mediated infectious disease caused by Mycobacterium tuberculosis, has been known to infect humans since ancient times. Although TB is common worldwide, the most recent report by the WHO (World Health Organization) listed the three countries of India, China, and Russia with 27%, 14%, and 8% of the global burden of TB, respectively. It has been reported that resistance to TB drugs, particularly by the pncA gene to the pyrazinamide drug due to mutations, significantly affects the effective treatment of TB. Understanding the mechanism of drug resistance using computational methods is of great interest to design effective TB treatment, exploring the structural features with these tools. Thus, keeping in view the importance of these methods, we employed state-of-the-art computational methods to study the mechanism of resistance caused by the W68L, L85P, and T87A mutations recently reported in 2021. We employed a molecular docking approach to predict the binding conformation and studied the dynamic properties of each complex using molecular dynamics simulation approaches. Our analysis revealed that compared to the wildtype, these three mutations altered the binding pattern and reduced the binding affinity. Moreover, the structural dynamic features also showed that these mutations significantly reduced the structural stability and packing, particularly by the W68L and L85P mutations. Moreover, principal component analysis, free energy landscape, and the binding free energy results revealed variation in the protein’s motion and the binding energy. The total binding free energy was for the wildtype −9.61 kcal/mol, W68L −7.57 kcal/mol, L85P −6.99 kcal/mol, and T87A −7.77 kcal/mol. Our findings can help to design a structure-based drug against the MDR (multiple drug-resistant) TB.

Structural and Dynamic Insights into the W68L, L85P, and T87A Mutations of Mycobacterium tuberculosis Inducing Resistance to Pyrazinamide