Structure-Based Design and Computational Validation of Novel 1,3,4-Thiadiazole-Peptide Conjugates as Selective Cyclin-Dependent Kinase-2 (CDK2) Inhibitors for Lung Cancer Therapy

Abstract

Lung cancer remains the leading cause of oncological mortality, necessitating the development of targeted therapies with improved precision. Cyclin-dependent kinase-2 (CDK2) is a pivotal regulator of the G1/S transition, making it a high-priority therapeutic target; however, achieving selectivity over other CDK isoforms remains a significant challenge. In this study, we report the design of a novel series of 1,3,4-thiadiazole-peptide conjugates using a structure-based hybrid pharmacophore approach. Computational screening via molecular docking identified TDP-4 as a lead candidate with a binding energy of −10.7 kcal/mol. 200-ns molecular dynamics (MD) simulations confirmed the stability of the TDP-4–CDK2 complex, maintained by persistent hydrogen bonds to hinge-region residues Leu83 and Glu81. Thermodynamic decomposition revealed synergistic enthalpic and entropic contributions, while cross-docking against CDK4 and CDK6 demonstrated enhanced isoform selectivity. Furthermore, ADMET profiling indicated favorable drug-likeness, reduced hepatotoxicity, and a predicted LD₅₀ of 1500 mg/kg. Importantly, resistance modeling suggested that the peptide moiety provides additional anchoring points, potentially mitigating the impact of common gatekeeper mutations. These findings position thiadiazole-peptide hybrids as a viable scaffold for the next generation of selective CDK2 inhibitors, offering translational potential in lung cancer therapy.