Molecular docking and dynamics reveal novel CDK6 inhibitors for targeted glioblastoma therapy

Glioblastoma multiform (GBM) is the most deadly type of primary CNS tumor and is linked to dysregulation of the CDK4/6 pathway, poor prognosis, and high rate of post-surgical recurrence. One practical strategy for overcoming treatment resistance in GBM is targeting CDK6. The main goal of this study was to identify new primary amine-containing compounds with specific inhibitory potential against CDK6 using in silico tools. A thorough in silico pipeline comprising ligand-based virtual screening (LBVS), molecular docking, ADMET, density functional theory (DFT) analysis, and molecular dynamics (MD) simulation was used in this investigation. First, molecular docking against CDK6 was performed on 109 bioactive compounds that had been screened using ligand-based virtual screening (LBVS). According to the docking analysis, 48 compounds exhibited more favorable Glide docking scores than the reference compound CCL (− 11.174 kcal·mol⁻¹), among which compound 21 showed the most favorable score (− 12.811 kcal·mol⁻¹). Additionally, the interaction study demonstrated that the target selectivity of compound 21 was improved by preferential interactions to the polar residues Lys43 and His100. Compound 21 satisfied Lipinski’s rule of five (LRo5) and exhibited a favorable predicted toxicity profile, along with predicted blood–brain barrier (BBB) permeability, based on analysis using the SwissADME online tool. Through the demonstration of the stability, moderate reactivity, and minimal off-target potential of compound 21, Density Functional Theory (DFT) studies provided additional validation for its electrical characteristics. Further molecular dynamics simulation straddling 250ns confirmed the stability and flexibility of compound 21. These findings demonstrated compound 21 as a predicted lead and it could serve as a potential therapeutic agent targeting CDK6 in GBM treatment. However, in vitro and in vivo studies are required for the further clinical application of compound 21.