Inhibiting Cyclin-Dependent Kinase 6 by Taurine: Implications in Anticancer Therapeutics

Abstract

Cyclin-dependent kinase 6 (CDK6) is linked with a cyclin partner and plays a crucial role in the early stages of cancer development. It is currently a potential drug target for developing therapeutic molecules targeting cancer therapy. Here, we have identified taurine as an inhibitor of CDK6 using combined in silico and experimental studies. We performed various experiments to find the binding affinity of taurine with CDK6. Molecular docking analysis revealed critical residues of CDK6 that are involved in taurine binding. Fluorescence measurement studies showed that taurine binds to CDK6 with a significant binding affinity, with a binding constant of K = 0.7 × 10 7 M –1 for the CDK6–taurine complex. Enzyme inhibition assay suggested taurine as a good inhibitor of CDK6 possessing an IC 50 value of 4.44 μM. Isothermal titration calorimetry analysis further confirmed a spontaneous binding of taurine with CDK6 and delineated the thermodynamic parameters for the CDK6–taurine system. Altogether, this study established taurine as a CDK6 inhibitor, providing a base for using taurine and its derivatives in CDK6-associated cancer and other diseases.

Modeling of Intracellular Taurine Levels Associated with Ovarian Cancer Reveals Activation of p53, ERK, mTOR and DNA-damage-sensing-dependent Cell Protection

“…Overexpression of p21 in OC cells mimicked taurine-induced inhibition of proliferation, further supporting the idea that taurine could potentially provide a strategy to inhibit OC cell proliferation through the activation of a major cell-cycle inhibitory pathway. Our data are consistent with recent in silico and cell-free biochemical studies 56 demonstrating that taurine can directly bind cyclin-dependent kinase 6 (CDK6). This interaction appears to inhibit CDK6 activity in solution, supporting the possibility that intracellular taurine accumulation could directly suppress CDK6/Cyclin D activity and arrest the cell cycle in G1 (demonstrated by our data).…”

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

“…Thus, by in silico analysis, fluorescence studies, and enzyme inhibition assay, they represented molecule 113 as a promising candidate against cancer (Baig et al, 2022). Yousuf et al (2022) identified taurine (114) (Fig. 24) as a potential CDK6 inhibitor using combined in silico and experimental studies.…”

“…This result was further confirmed by fluorescence measurement studies for the CDK6-114 complex. Enzyme inhibition assay showed the IC 50 value of 4.44 μM, and isothermal titration calorimetric analysis indicated the spontaneous binding of taurine with CDK6 (Yousuf et al, 2022). Lotlikar et al (2021) synthesized and characterized 10 Schiff's bases of 2,7-diamino-2′-oxospiro [chromene-4,3′-indoline]-3-carbonitrile.…”

Targeting Human progesterone receptor (PR), through Pharmacophore- based screening and molecular simulation revealed potent inhibitors against breast cancer

“…The surface area contributions quantify the change in solvent-accessible surface area (SASA) upon ligand binding, considering alterations in hydrophobic and polar interactions. By combining these components, MM/GBSA provides a comprehensive approach for predicting and analyzing the binding free energies of protein-ligand complexes [39][40][41][42].…”