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

Gaomin Zhang,Yujie Ren

doi:10.3390/molecules23112924

Gaomin Zhang, Yujie Ren

Open Access

https://doi.org/10.3390/molecules23112924

Copy DOI

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, = 0.991), the CoMSIA model (q2 = 0.808, = 0.990), and the Topomer CoMFA model (q2 = 0.779, = 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.

Highlights

Cancer is a serious threat to human health and the sustained cellular proliferation has been considered a key hallmark of cancer [1]
Cyclin-dependent kinase 2 (CDK2) that intervenes in the cell cycle at the G1 and S phases is an important member of the cyclin-dependent kinases (CDKs) family
During the S phase, CDK2 binds to cyclin A to promote the phosphorylation and inactivation of E2F, which results in S phase

Summary

Introduction

Cancer is a serious threat to human health and the sustained cellular proliferation has been considered a key hallmark of cancer [1]. The proliferation of mammalian cells is controlled by the cell cycle in which cyclin-dependent kinases (CDKs) regulate the critical phases [2,3]. CDKs are a group of enzymes that directly regulate the orderly completion of the cell cycle [4]. The human genome encodes 21 CDKs, which typically need to associate with the corresponding cyclins to be active [5]. CDK2 that intervenes in the cell cycle at the G1 and S phases is an important member of the CDK family. During the G1 phase, CDK2 paired with cyclin E leads to hyperphosphorylation of the retinoblastoma tumor suppressor protein (Rb), which causes full release of the suppression of the E2F family of transcription factors, which drives cells into the G1/S transition. During the S phase, CDK2 binds to cyclin A to promote the phosphorylation and inactivation of E2F, which results in S phase

Methods

Results

Conclusion