TAGRA 2025

Glioma progression is driven by dysregulated signaling networks, including CDK4-Cyclin D3, PI3K-Akt, and EGFR pathways. Targeting CDK4-Cyclin D3 offers a promising therapeutic strategy. A systems-level computational approach was employed to identify potential CDK4-Cyclin D3 inhibitors from the OTAVA library. Network pharmacology, molecular docking, MMGBSA, AutoQSAR modeling, Density function theory (DFT) calculations, drug-likeness and ADMET profiling, and 200 ns molecular dynamics simulations were performed alongside temozolomide as a reference. Network analysis identified 16 shared glioma targets for vorasidenib and temozolomide, highlighting central pathways regulating metabolism, cell survival, and DNA repair. Docking and MMGBSA analyses revealed Compounds 781, 792, and 2299 as potent CDK4-Cyclin D3 inhibitors, outperforming temozolomide. AutoQSAR predicted higher pIC₅₀ values for the hits, with Compound 781 ranked highest. DFT calculations indicated favorable electronic properties for protein-ligand interactions. Drug-likeness and pharmacokinetic profiling demonstrated good oral absorption, moderate blood brain barrier (BBB) permeability, and acceptable cardiotoxicity. Molecular dynamics simulations at 200 ns demonstrated stable binding, minimal structural fluctuations, and strong hydrogen bond, particularly for Compound 781. Compounds 781, 792, and 2299 have higher predicted potency, binding stability, and favorable pharmacokinetic properties than temozolomide, indicating their potential as CDK4-Cyclin D3 inhibitors for glioma treatment. These computational insights provide a strong rationale for experimental validation in vitro and in vivo.