Kamil R F, Debnath U, Verma S, Prabhakar Y S
R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, India.
Department of Pharmaceutical Chemistry, Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata 700114, India.
Curr HIV Res. 2018;16(2):121-129. doi: 10.2174/1570162X16666180412165004.
A possible strategy to combat mutant strains is to have a thorough structural evaluation before and after mutations to identify the diversity in the non-nucleoside inhibitor binding pocket and their effects on enzyme-ligand interactions to generate novel NNRTI's accordingly.
The primary objective of this study was to find effects of multiple point mutations on NNRTI binding pocket. This study included the contribution of each individual mutation in NNIBP that propose an adjacent binding pocket which can be used to discover novel NNRTI derivatives.
An in Silico model of HIV-1 RT enzyme with multiple mutations K103N, Y181C and Y188L was developed and evaluated. Two designed NNRTI pyridinone derivatives were selected as ligands for docking studies with the homology model through alignment based docking and residue based docking approaches. Binding pockets of wild type HIV-1 RT and multi-mutated homology model were compared thoroughly.
K103N mutation narrowed the entrance of NNRTI binding pocket and forbade electrostatic interaction with α amino group of LYS103. Mutations Y181C and Y188L prevented NNRTI binding by eliminating aromatic π interactions offered by tyrosine rings. Docking study against new homology model suggested an adjacent binding pocket with combination of residues in palm and connection domains. This pocket is approximately 14.46Å away from conventional NNRTI binding site.
Increased rigidity, steric hindrance and losses of important interactions cumulatively prompt ligands to adapt adjacent NNRTI binding pocket. The proposed new and adjacent binding pocket is identified by this study which can further be evaluated to generate novel derivatives.
对抗突变株的一种可能策略是在突变前后进行全面的结构评估，以确定非核苷抑制剂结合口袋中的多样性及其对酶-配体相互作用的影响，从而相应地生成新型非核苷类逆转录酶抑制剂（NNRTI）。
本研究的主要目的是发现多点突变对NNRTI结合口袋的影响。本研究包括NNIBP中每个单独突变的贡献，该贡献提出了一个相邻的结合口袋，可用于发现新型NNRTI衍生物。
开发并评估了具有多个突变K103N、Y181C和Y188L的HIV-1逆转录酶的计算机模拟模型。选择两种设计的NNRTI吡啶酮衍生物作为配体，通过基于比对的对接和基于残基的对接方法与同源模型进行对接研究。对野生型HIV-1逆转录酶和多突变同源模型的结合口袋进行了全面比较。
K103N突变使NNRTI结合口袋的入口变窄，并阻止了与LYS103的α氨基的静电相互作用。Y181C和Y188L突变通过消除酪氨酸环提供 的芳香π相互作用来阻止NNRTI结合。针对新同源模型的对接研究表明，在手掌和连接域中存在一个由残基组合而成的相邻结合口袋。该口袋距离传统的NNRTI结合位点约14.46Å。
刚性增加、空间位阻和重要相互作用的丧失共同促使配体适应相邻的NNRTI结合口袋。本研究确定了所提出的新的相邻结合口袋，可进一步评估以生成新型衍生物。
