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Molecules 2018, 23(11), 2924; https://doi.org/10.3390/molecules23112924

Molecular Modeling and Design Studies of Purine Derivatives as Novel CDK2 Inhibitors

School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China
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Academic Editor: Kok Hwa Lim
Received: 23 September 2018 / Revised: 29 October 2018 / Accepted: 6 November 2018 / Published: 9 November 2018
(This article belongs to the Special Issue QSAR and QSPR: Recent Developments and Applications)
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Abstract

Cyclin-dependent kinase 2 (CDK2) is a potential target for treating cancer. Purine heterocycles have attracted particular attention as the scaffolds for the development of CDK2 inhibitors. To explore the interaction mechanism and the structure–activity relationship (SAR) and to design novel candidate compounds as potential CDK2 inhibitors, a systematic molecular modeling study was conducted on 35 purine derivatives as CDK2 inhibitors by combining three-dimensional quantitative SAR (3D-QSAR), virtual screening, molecular docking, and molecular dynamics (MD) simulations. The predictive CoMFA model (q2 = 0.743, r pred 2 = 0.991), the CoMSIA model (q2 = 0.808, r pred 2 = 0.990), and the Topomer CoMFA model (q2 = 0.779, r pred 2 = 0.962) were obtained. Contour maps revealed that the electrostatic, hydrophobic, hydrogen bond donor and steric fields played key roles in the QSAR models. Thirty-one novel candidate compounds with suitable predicted activity (predicted pIC50 > 8) were designed by using the results of virtual screening. Molecular docking indicated that residues Asp86, Glu81, Leu83, Lys89, Lys33, and Gln131 formed hydrogen bonds with the ligand, which affected activity of the ligand. Based on the QSAR model prediction and molecular docking, two candidate compounds, I13 and I60 (predicted pIC50 > 8, docking score > 10), with the most potential research value were further screened out. MD simulations of the corresponding complexes of these two candidate compounds further verified their stability. This study provided valuable information for the development of new potential CDK2 inhibitors. View Full-Text
Keywords: CDK2; 3D-QSAR; virtual screening; molecular docking; lead compound optimization; molecular dynamics CDK2; 3D-QSAR; virtual screening; molecular docking; lead compound optimization; molecular dynamics
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Zhang, G.; Ren, Y. Molecular Modeling and Design Studies of Purine Derivatives as Novel CDK2 Inhibitors. Molecules 2018, 23, 2924.

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