Title: Characterisation of the flexibility of substrate binding loop in the binding of direct InhA inhibitors

Authors: Vivek Kumar; M. Elizabeth Sobhia

Addresses: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India ' Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India

Abstract: The substrate binding loop (SBL) of inhA shows conformational changes on binding of direct inhA inhibitors (DIIs). The knowledge of conformational changes and its importance in binding of DII to inhA has not been explored before. This study initially focused on studying the conformational changes of SBL in selected inhA crystal structures. These conformational changes are measured as angle of rotation for SBL from the static hinge region, Ile194, in the crystal structures. The maximal angle difference of ∼41° was observed between most open and closed conformation of SBL. To gain insights into these conformational changes, comparative molecular dynamics simulations of inhA bound with a direct inhibitor (Genz10850) and apoprotein were performed. A considerable variation in the angle of rotation (∼24° to ∼12°) for the SBL which led to the closed conformation was observed during binding of Genz10850 with a consistent increase in electrostatic energy, whereas no change was observed in apoprotein. Hence, conformational changes in the SBL under the influence of inhibitor can be utilised as a parameter for enhanced binding inhibitor with inhA to screen the potent DIIs.

Keywords: tuberculosis; MDR-TB/XDR-TB; InhA inhibitors; crystal structure; B-factor; molecular dynamics; simulation; binding free energy; molecular docking; substrate binding loop; angle of rotation.

DOI: 10.1504/IJCBDD.2013.056795

International Journal of Computational Biology and Drug Design, 2013 Vol.6 No.4, pp.318 - 342

Received: 25 Apr 2012
Accepted: 18 Dec 2012

Published online: 27 Aug 2013 *

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