Polyphenol MHQP as an allosteric inhibitor of Kinesin-5: Cease the molecular catwalk of “Drunken Sailor”

IF 1.5 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Indian journal of biochemistry & biophysics Pub Date : 2023-01-01 DOI:10.56042/ijbb.v60i9.4056

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引用次数: 0

Abstract

Human Kinesin-5 (KIF-11/Eg5), a major anticancer drug target, is a plus end-directed motor protein that is involved in spindle dynamics and principally involved in mitosis. In the present study, a computer-aided rational drug discovery approach has been applied to search for potential allosteric inhibitors against Eg5. Accordingly, virtual screening of naturally occurring secondary metabolites and their commercially available synthetic derivatives indicates 2-(9b- methyl-2,3,3a,4,5,9b-hexahydrofuro [3,2 c] quinolin-4-yl) phenol (MHQP), a hexahydrofuro [3,2-c] quinolone derivative as a potential therapeutic lead molecule against Eg5. The present study provides a structural glimpse of MHQP binding at the monastrol binding site of Eg5 with a vivid description of its plausible mode of Eg5 inhibition. Moreover, the in silico data also supports the superiority of MHQP over the well-characterized Eg5 inhibitor Arry-520 in terms of augmented binding affinity as well as to cope with Arry-520 resistant mutants of Eg5. Structure-guided mechanistic details of MHQP-induced inhibition of Eg5 and its predicted pharmacodynamics properties have been presented herein.

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多酚MHQP作为kineins -5变构抑制剂:停止“醉酒水手”的分子走秀

人类运动蛋白-5 (KIF-11/Eg5)是一种主要的抗癌药物靶点，是一种正端定向运动蛋白，参与纺锤体动力学，主要参与有丝分裂。在本研究中，计算机辅助的合理药物发现方法已被应用于寻找潜在的抗Eg5变构抑制剂。因此，对天然次生代谢产物及其商业合成衍生物的虚拟筛选表明，2- (9b-甲基-2,3,3a,4,5,9b-六氢呋喃[3,2c]喹诺酮-4-基)苯酚(MHQP)是一种六氢呋喃[3,2c]喹诺酮衍生物，可能是治疗Eg5的潜在先导分子。本研究提供了MHQP在Eg5的monastrol结合位点结合的结构一瞥，并生动地描述了其抑制Eg5的合理模式。此外，计算机数据还支持MHQP在增强结合亲和力以及应对Eg5的Arry-520耐药突变体方面优于已被充分表征的Eg5抑制剂Arry-520。本文介绍了mhqp诱导的Eg5抑制的结构导向机制细节及其预测的药效学性质。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Indian journal of biochemistry & biophysics 生物-生化与分子生物学

CiteScore

2.90

自引率

50.00%

发文量

审稿时长

3 months

期刊介绍： Started in 1964, this journal publishes original research articles in the following areas: structure-function relationships of biomolecules; biomolecular recognition, protein-protein and protein-DNA interactions; gene-cloning, genetic engineering, genome analysis, gene targeting, gene expression, vectors, gene therapy; drug targeting, drug design; molecular basis of genetic diseases; conformational studies, computer simulation, novel DNA structures and their biological implications, protein folding; enzymes structure, catalytic mechanisms, regulation; membrane biochemistry, transport, ion channels, signal transduction, cell-cell communication, glycobiology; receptors, antigen-antibody binding, neurochemistry, ageing, apoptosis, cell cycle control; hormones, growth factors; oncogenes, host-virus interactions, viral assembly and structure; intermediary metabolism, molecular basis of disease processes, vitamins, coenzymes, carrier proteins, toxicology; plant and microbial biochemistry; surface forces, micelles and microemulsions, colloids, electrical phenomena, etc. in biological systems. Solicited peer reviewed articles on contemporary Themes and Methods in Biochemistry and Biophysics form an important feature of IJBB. Review articles on a current topic in the above fields are also considered. They must dwell more on research work done during the last couple of years in the field and authors should integrate their own work with that of others with acumen and authenticity, mere compilation of references by a third party is discouraged. While IJBB strongly promotes innovative novel research works for publication as full length papers, it also considers research data emanating from limited objectives, and extension of ongoing experimental works as ‘Notes’. IJBB follows “Double Blind Review process” where author names, affiliations and other correspondence details are removed to ensure fare evaluation. At the same time, reviewer names are not disclosed to authors.