Comparative Structure-Based Molecular Docking Analysis of Clinically Approved CDK4/6 Inhibitors Targeting CDK6

Structure-Based Design and Evaluation of Coumarin-Derived CDK4 Inhibitors for Non-Small Cell Lung Cancer: An Integrated Computational Study.

Findings establish coumarin-derived scaffolds as promising starting points for the development of next-generation CDK4-targeted therapeutics and provide a strong computational foundation for future experimental validation in NSCLC.

Discovery of Potent CDK2 Inhibitors Through Structure-Based Virtual Screening and MD Simulation Studies.

Overall, MD1-MD5 demonstrated excellent binding, structural stability, and pharmacokinetic properties, making them strong candidates for future CDK2-targeted anticancer research.

An Integrated Computational Workflow for Discovering Alkaloid-Derived Ligands of Cyclin-Dependent Kinase 2

Background/Objectives: Cyclin-dependent kinase 2 (CDK2) is a key regulator of cell-cycle progression and a potential anticancer target. This study aimed to identify alkaloid-derived CDK2 ligands using an integrated computational workflow and to obtain preliminary evidence of their effects on cancer-cell viability. Methods: Molecular docking with mVina and fast pulling of ligand (FPL) simulations were benchmarked using 20 experimentally characterized CDK2 inhibitors. A library of 2692 PubChem-derived alkaloids was screened, followed by ADMET evaluation, 100 ns molecular dynamics simulations, and FPL-based relative-affinity re-ranking. The three prioritized compounds were evaluated in HepG2 and HGC-27 cells using an MTT assay after 48 h of exposure. Results: Docking and FPL showed correlations with experimental affinity data of RDock = 0.549 ± 0.180 and RW = −0.676 ± 0.119, respectively. CID 636885, CID 46184320, and CID 101691758 were prioritized for detailed evaluation. All three compounds reduced cell viability, with lower IC50 values observed in HepG2 cells than in HGC-27 cells. CID 101691758 exhibited the highest growth-inhibitory activity among the tested compounds, with IC50 values of 15.37 ± 0.46 µg mL−1 in HepG2 cells and 52.64 ± 1.33 µg mL−1 in HGC-27 cells. Conclusions: The workflow identified three preliminary alkaloid hits, with CID 101691758 showing the most favorable combined computational and cell-viability profile. However, the MTT assay does not establish direct CDK2 inhibition or kinase selectivity. Biochemical CDK2 inhibition, target-engagement, and kinase-panel studies are therefore required.

Pharmacophore-based identification and molecular docking of CCR5 inhibitors: insights from dynamic simulations

The integrated computational approach identified ZINC000000867238 as a potent and stable CCR5 inhibitor candidate, warranting further in vitro and in vivo validation as a potential HIV-1 entry blocker.

CDK4/6-Based Drug Research and Development: A Four-Year Update.

INTRODUCTION CDK4/6 kinases are crucial cell cycle regulators, and pharmacological inhibition of these kinases to block the G1-to-S phase transition has become an integral part of modern cancer therapy. Although five CDK4/6 inhibitors have been clinically approved, the development of acquired drug resistance greatly limits their long-term therapeutic efficacy. METHODS This review systematically summarizes the latest advances in CDK4/6 inhibitor research from 2022 to 2025, focusing on their structural features, biological functions, and preclinical research progress. In addition, this article comprehensively explores emerging therapeutic strategies, including bifunctional molecules and PROTAC-based protein degraders. RESULTS The action mechanisms of conventional CDK4/6 inhibitors have been relatively well elucidated. Notably, these emerging strategies have yielded encouraging preclinical results, including co-targeting CDK4/6 with other critical therapeutic nodes (e.g., HDAC, PARP1) and adopting PROTAC-based degraders to directly induce the degradation of target proteins. A growing number of innovative approaches targeting drug resistance via multi-target inhibition and induced protein degradation have been developed. Distinct from classical singletarget monotherapy, these innovative strategies leverage distinct pharmacological pathways, offering feasible research directions to improve therapeutic efficacy and delay drug resistance. DISCUSSION In-depth understanding of CDK4/6 inhibitors and the continuous development of bifunctional agents and protein degraders provides key theoretical and technical support for the design of next-generation therapeutic strategies to address current clinical limitations. These research advances are expected to facilitate the development of more effective and long-lasting therapeutic modalities for tumor treatment. CONCLUSION This review summarizes recent advances in CDK4/6 inhibitors. Novel dual-target and PROTACbased strategies offer promising resistance-overcoming tumor therapies.

Harnessing machine learning, docking and molecular dynamics for the virtual screening of compounds as CDK4/6 dual inhibitors.