Selective Cyclin-Dependent Kinase Inhibitors for Cancer Therapy: A Narrative Review of Molecular Docking Insights from Natural, Synthetic, and Hybrid Scaffolds
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Abstract
Cyclin-dependent kinases (CDKs) regulate cell-cycle progression, transcription, and genomic stability. Their dysregulation contributes to cancer development and therapeutic resistance, but the conserved ATP-binding architecture of CDKs complicates the development of isoform-selective inhibitors. This review aimed to compare molecular docking-guided design strategies across natural, synthetic, semi-synthetic, and hybrid scaffolds, identify determinants of CDK selectivity, and evaluate the progression of computational candidates toward experimental and clinical validation. A narrative review was conducted from 1 November 2025 to 31 January 2026. PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for relevant publications issued from January 2020 to January 2026. Evidence was synthesised thematically according to scaffold class, docking methodology, structural selectivity, and biochemical, cellular, in vivo, or clinical validation. Synthetic scaffolds provided the clearest basis for iterative structure–activity optimisation and experimental validation. Natural products expanded chemical diversity but were frequently supported only by computational or cytotoxicity evidence, while semi-synthetic and hybrid scaffolds offered opportunities for pharmacological optimisation. Potency was mainly associated with conserved hinge binding, whereas selectivity appeared to depend on peripheral or allosteric interactions and conformational differences. Docking scores alone did not establish affinity, target engagement, or isoform selectivity. Molecular docking should be integrated with comparative enzyme assays, kinome profiling, cellular target-engagement studies, and pharmacokinetic and in vivo evaluation to guide the development of clinically relevant, resistance-aware CDK inhibitors.
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