Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

Abstract

Cell cycle dysregulation is a characteristic hallmark of malignancies, which results in uncontrolled cell proliferation and eventual tumor formation. Cyclin-dependent kinase 1 (CDK1) is a member of the family of cell cycle regulatory proteins involved in cell cycle maintenance. Given that overexpression of CDK1 has been associated with cancer, CDK1 inhibitors may restore equilibrium to the skewed cell cycle system and operate as an effective therapeutic drug. This study aimed to identify and classify inhibitors having a higher affinity for CDK1 and also evaluate the expression pattern and prognostic relevance of CDK1 in a wide range of cancers. We investigated therapeutic molecules structurally similar to dinaciclib for their ability to inhibit CDK1 selectively. To assess the therapeutic potential of screened Dinaciclib analogs, we used drug likeliness analysis, molecular docking, and simulation analysis. CDK1 was found to be highly upregulated across several malignancies and is associated with poor overall and relapse-free survival. Molecular docking and dynamics evaluation identified two novel dinaciclib analogs as potent CDK1 inhibitors with high binding affinity and stability compared to dinaciclib. The results indicate that increased CDK1 expression is associated with decreased OS and RFS. Additionally, dinaciclib analogs are prospective replacements for dinaciclib since they exhibit increased binding affinity, consistent with MDS findings, and have acceptable ADMET qualities. The discovery of new compounds may pave the road for their future application in cancer prevention through basic, preclinical, and clinical research. Supplementary Information The online version contains supplementary material available at 10.1007/s12032-022-01748-2.

Adapalene inhibits the growth of triple-negative breast cancer cells by S-phase arrest and potentiates the antitumor efficacy of GDC-0941

“…The results were validated both in silico and in vitro . CDK2 is upregulated in breast tumors, and its vital role in cell cycle regulation makes CDK2 an attractive therapeutic target ( Sofi et al, 2022a ; Mehraj et al, 2022e ; Mehraj et al, 2022f ). Together, these results demonstrate that ADA has high potential in reducing tumor growth and colonization of TNBC cells.…”

CDK1 as a Novel Potential Biomarker for Predicting the Prognosis of endometrioid ovarian carcinoma

“…This overexpression has also been observed in other cancer types, such as hepatocellular carcinoma 12 , pancreatic adenocarcinoma 6,14 , esophageal adenocarcinoma 33 and lung adenocarcinoma 34 , as demonstrated by multiple database analyses. The elevated expression of CDK1 is significant across pan-cancers 35 .…”

A comprehensive analysis of the role of molecular docking in the development of anticancer agents against the cell cycle CDK enzyme

“…Therefore, it is important to design potent CDK1 inhibitors. In this regard, Sofi et al (2022) target the CDK1 enzyme using dinaciclib analogs by employing molecular docking (AutoDock 4.2.6) and molecular dynamics simulations (Desmond 2020.1, Schrödinger). They retrieved 100 dinaciclib analogs from the online PubChem database, which were further analyzed for their drug-likeness and ADMET properties.…”

“…Based on the stable simulation outcome, their novelty was checked using ChemSpider. Thus, they utilized in silico methods to validate the CDK1 as a therapeutic target and evaluate the inhibitory activity of the dinaciclib analogs (Sofi et al, 2022).…”