Publication Type Journal Article
Title Molecular Details of INH-C-10 Binding to wt KatG and Its S315T Mutant
Authors Vitor H. Teixeira Cristina Ventura R. Elvas-Leitão Clara Rafols Elisabeth Bosch F. Martins Miguel Machuqueiro
Groups MET
Journal MOLECULAR PHARMACEUTICS
Year 2015
Month March
Volume 12
Number 3
Pages 898-909
Abstract Isoniazid (INH) is still one of the two most effective antitubercular drugs and is included in all recommended multitherapeutic regimens. Because of the increasing resistance of Mycobacterium tuberculosis to INH, mainly associated with mutations in the katG gene, new INH-based compounds have been proposed to circumvent this problem. In this work, we present a detailed comparative study of the molecular determinants of the interactions between wt KatG or its S315T mutant form and either INH or INH-C-10, a new acylated INH derivative. MD simulations were used to explore the conformational space of both proteins, and results indicate that the S315T mutation did not have a significant impact on the average size of the access tunnel in the vicinity of these residues. Our simulations also indicate that the steric hindrance role assigned to Asp137 is transient and that electrostatic changes can be important in understanding the enzyme activity data of mutations in KatG. Additionally, molecular docking studies were used to determine the preferred modes of binding of the two substrates. Upon mutation, the apparently less favored docking solution for reaction became the most abundant, suggesting that S315T mutation favors less optimal binding modes. Moreover, the aliphatic tail in INH-C-10 seems to bring the hydrazine group closer to the heme, thus favoring the apparent most reactive binding mode, regardless of the enzyme form. The ITC data is in agreement with our interpretation of the C-10 alkyl chain role and helped to rationalize the significantly lower experimental MIC value observed for INH-C-10. This compound seems to be able to counterbalance most of the conformational restrictions introduced by the mutation, which are thought to be responsible for the decrease in INH activity in the mutated strain. Therefore, INH-C-10 appears to be a very promising lead compound for drug development.
DOI http://dx.doi.org/10.1021/mp500736n
ISBN
Publisher
Book Title
ISSN 1543-8384
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Conference Name
Bibtex ID ISI:000350390900023
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