Treatment of Tuberculosis

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Tuberculosis continues to be a global health threat. <scene name='Journal:JBSD:11/Cv/6'>Pyrazinamide (PZA)</scene> is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to pyrazinamide represents an important public health problem, as both first- and second-line treatment regimens include pyrazinamide. It becomes toxic to ''Mycobacterium tuberculosis'' when converted to pyrazinoic acid by the <scene name='Journal:JBSD:11/Cv/5'>bacterial pyrazinamidase (PncA) enzyme</scene>. PZA resistance is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are resistance for PZA</scene>. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three dimensional conformational behaviour of <scene name='Journal:JBSD:11/Cv/3'>native</scene> and mutants PncA. Our analysis clearly indicates that the mutation (<scene name='Journal:JBSD:11/Cv/8'>D8G</scene>, <scene name='Journal:JBSD:11/Cv/9'>S104R</scene> and <scene name='Journal:JBSD:11/Cv/10'>C138Y</scene>) in PncA is responsible for rigid binding cavity which in turns abolishes conversion of PZA to its active form and is the sole reason for PZA resistance. Excessive hydrogen bonding between PZA binding cavity residues and their neighboring residues are the reason of rigid binding cavity during simulation. We present an exhaustive analysis of the binding-site flexibility and its 3D conformations that may serve as new starting points for structure-based drug design and helps there researchers to design new inhibitor with consideration of rigid criterion of binding residues due to mutation of this essential target.

Tuberculosis continues to be a global health threat. <scene name='Journal:JBSD:11/Cv/6'>Pyrazinamide (PZA)</scene> is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to pyrazinamide represents an important public health problem, as both first- and second-line treatment regimens include pyrazinamide. It becomes toxic to ''Mycobacterium tuberculosis'' when converted to pyrazinoic acid by the <scene name='Journal:JBSD:11/Cv/5'>bacterial pyrazinamidase (PncA) enzyme</scene>. PZA resistance is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are resistance for PZA</scene>. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three dimensional conformational behaviour of <scene name='Journal:JBSD:11/Cv/3'>native</scene> and mutants PncA. Our analysis clearly indicates that the mutation (<scene name='Journal:JBSD:11/Cv/8'>D8G</scene>, <scene name='Journal:JBSD:11/Cv/9'>S104R</scene> and <scene name='Journal:JBSD:11/Cv/10'>C138Y</scene>) in PncA is responsible for rigid binding cavity which in turns abolishes conversion of PZA to its active form and is the sole reason for PZA resistance. Excessive hydrogen bonding between PZA binding cavity residues and their neighboring residues are the reason of rigid binding cavity during simulation. We present an exhaustive analysis of the binding-site flexibility and its 3D conformations that may serve as new starting points for structure-based drug design and helps there researchers to design new inhibitor with consideration of rigid criterion of binding residues due to mutation of this essential target.

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