3D-QSAR Studies of Dihydropyrazole and Dihydropyrrole Derivatives as Inhibitors of Human Mitotic Kinesin Eg5 Based on Molecular Docking

Xingyan Luo,Yuanqiang Wang,Mao Shu,Jin Liu,Wenjuan Yang,Zhihua Lin

doi:10.3390/molecules17022015

Abstract

Human mitotic kinesin Eg5 plays an essential role in mitoses and is an interesting drug target against cancer. To find the correlation between Eg5 and its inhibitors, structure-based 3D-quantitative structure–activity relationship (QSAR) studies were performed on a series of dihydropyrazole and dihydropyrrole derivatives using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Based on the LigandFit docking results, predictive 3D-QSAR models were established, with cross-validated coefficient values (q2) up to 0.798 for CoMFA and 0.848 for CoMSIA, respectively. Furthermore, the CoMFA and CoMSIA models were mapped back to the binding sites of Eg5, which could provide a better understanding of vital interactions between the inhibitors and the kinase. Ligands binding in hydrophobic part of the inhibitor-binding pocket were found to be crucial for potent ligand binding and kinases selectivity. The analyses may be used to design more potent EG5 inhibitors and predict their activities prior to synthesis.

Highlights

The human mitotic kinesin Eg5 is one member of the Kinesin-5 subfamily, which function is helping the formation of bipolar mitotic spindle, and has been identified as a potential target for new drug development in cancer chemotherapy [1]
As multidrug resistance (MDR) of anticancer drug like taxanes and vinca alkaloids has become a serious problem in cancer chemotherapy [10,11], the Eg5 inhibitors have been tested for their susceptibility to the PgP efflux pump and some of them have been validated for greater potential to overcome
We examine the three dimensional quantitative structure-activity relationships (3D-quantitative structure–activity relationship (QSAR)) using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) [24,25,26,27,28,29,30] and molecular docking (LigandFit Docking [31]) analyses, that provide insinhts into the relationship between the structural information of dihydropyrazole and dihydropyrrole inhibitors and their inhibitory potency, aimed at providing valuable guidance for the design of EG5 inhibitor compounds with highly anticancer activity

Summary

Introduction

The human mitotic kinesin Eg5 is one member of the Kinesin-5 subfamily, which function is helping the formation of bipolar mitotic spindle, and has been identified as a potential target for new drug development in cancer chemotherapy [1]. The compounds were used under the same conditions of an in vitro screening procedure based on the inhibition of the ATP kinase activity of Eg5, which like STLC leads to mitotic arrest by slowing ADP release from the catalytic site of Eg5 so that induces cancer cell death by the apoptotic pathway [19]. Some of these inhibitors showed good potency in Pgp-overexpressing cells

Methods

Results

Conclusion