Kumar Vivek, Sobhia M Elizabeth
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India.
Int J Comput Biol Drug Des. 2013;6(4):318-42. doi: 10.1504/IJCBDD.2013.056795. Epub 2013 Sep 30.
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.
InhA 的底物结合环（SBL）在直接 InhA 抑制剂（DIIs）结合时会发生构象变化。此前尚未探究过构象变化及其在 DII 与 InhA 结合中的重要性。本研究最初聚焦于研究选定 InhA 晶体结构中 SBL 的构象变化。这些构象变化通过晶体结构中 SBL 相对于静态铰链区 Ile194 的旋转角度来衡量。在 SBL 的最开放和最闭合构象之间观察到约 41°的最大角度差异。为深入了解这些构象变化，对与直接抑制剂（Genz10850）结合的 InhA 和脱辅基蛋白进行了比较分子动力学模拟。在 Genz10850 结合过程中，观察到 SBL 导致闭合构象的旋转角度有相当大的变化（约 24°至约 12°），同时静电能持续增加，而脱辅基蛋白则未观察到变化。因此，抑制剂影响下 SBL 的构象变化可作为增强抑制剂与 InhA 结合的参数，用于筛选有效的 DIIs。
