The Quest for Ligands Against Kinesin Motor Protein Eg5

IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL
Ahmet Fatih Sahin, Simone Carradori, Alessia Ricci, Muhammad Rashad, Atilla Akdemir
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引用次数: 0

Abstract

The Kinesin Eg5 motor protein is essential for the formation of the mitotic spindles and chromosome segregation, which is necessary for cell division. The inhibition of Eg5 has emerged as a potential therapeutic strategy for inhibiting the uncontrolled proliferation of cancer cells. This study aims to identify inhibitors targeting the allosteric site I of Eg5. To this end, a hierarchical virtual screening was applied to screen the ZINC20-Anodyne compound library comprising approximately 11 million druglike compounds. The procedure includes a shape similarity screening, a pharmacophore screening, docking studies with subsequent re-scorings, molecular dynamics simulations, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations and resulted in the selection of four compounds for Eg5 inhibition assays. One compound displays an IC50 value of 29 µM, while the remaining three compounds show weaker inhibition of Kinesin Eg5. As such, structurally novel Kinesin Eg5 inhibitors have been obtained for further hit-to-lead optimization programs.

寻找对抗运动蛋白Eg5的配体
运动蛋白Eg5对有丝分裂纺锤体的形成和染色体分离至关重要,这是细胞分裂所必需的。抑制Eg5已成为抑制癌细胞不受控制的增殖的潜在治疗策略。本研究旨在寻找靶向Eg5变构位点I的抑制剂。为此,采用分层虚拟筛选方法筛选包含约1100万种药物样化合物的ZINC20-Anodyne化合物库。该过程包括形状相似性筛选、药效团筛选、对接研究以及随后的重新评分、分子动力学模拟和分子力学-广义出生表面积(MM-GBSA)结合自由能计算,最终选择了四种化合物用于Eg5抑制试验。其中1个化合物的IC50值为29µM,其余3个化合物对Kinesin Eg5的抑制作用较弱。因此,结构新颖的Kinesin Eg5抑制剂已被获得,用于进一步的hit-to-lead优化程序。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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