Drug Design of Cyclin-Dependent Kinase 2 Inhibitor for Melanoma from Traditional Chinese Medicine

Abstract

One has found an important cell cycle controller. This guard can decide the cell cycle toward proliferation or quiescence. Cyclin-dependent kinase 2 (CDK2) is a unique target among the CDK family in melanoma therapy. We attempted to find out TCM compounds from TCM Database@Taiwan that have the ability to inhibit the activity of CDK2 by systems biology. We selected Tetrahydropalmatine, Reserpiline, and (+)-Corydaline as the candidates by docking and screening results for further survey. We utilized support vector machine (SVM), multiple linear regression (MLR) models and Bayesian network for validation of predicted activity. By overall analysis of docking results, predicted activity, and molecular dynamics (MD) simulation, we could conclude that Tetrahydropalmatine, Reserpiline, and (+)-Corydaline had better binding affinity than the control. All of them had the ability to inhibit the activity of CDK2 and might have the opportunity to be applied in melanoma therapy.

A Comprehensive Review on the Chemical Properties, Plant Sources, Pharmacological Activities, Pharmacokinetic and Toxicological Characteristics of Tetrahydropalmatine

“…A recent study confirmed that THP can treat glioblastoma multiforme by inhibiting the ERK/NF-κB cascade ( Xue and Chen, 2021 ). THP is effective in treating melanoma by inhibiting the activity of CDK2, which is a unique target among the CDK family members in melanoma therapy ( Tang and Chen, 2014 ). In ovarian cancer A2780/DDP cell line, THP can increase the sensitivity of ovarian cancer cells to cisplatin by regulating the miR-93/PTEN/AKT pathway ( Gong et al, 2019 ).…”

Biological activity, quantitative structure–activity relationship analysis, and molecular docking of xanthone derivatives as anticancer drugs

“…It is believed that Arg 86 is an important residue in the CDK2 inhibition mechanism. 47 These results are also supported by the finding that Lys 33 , Arg 88 , and Asp 145 are involved in polar interactions and have a significant site role in CDK2 inhibition and that Leu 83 is part of the hinge interaction site. 48 Thus, hydrogen bonds of the given amino acid residues had an important role in the catalytic activity of CDK2 inhibition.…”

Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine

“…Traditional Chinese medicine (TCM) has been widely used to relieve and treat various cancers and tumors with good effects and lower side-effects [9,10]. A number of ingredients of TCM have been reported as having efficacy by interacting with the allosteric site [11].…”

“…In recent years, molecular simulation technologies, such as molecular docking, pharmacophore model, and molecular dynamics were used to discover new drugs from TCM and elucidate the mechanism at the molecular level [13]. For instance, Tang et al discovered several CDK2 ATP-competitive inhibitors from TCM by using molecular docking and molecular dynamics [9]. However, the discovery of pure CDK2 allosteric inhibitors from TCM has not been carried out.…”