In silico identification of novel CDK4 inhibitors for retinoblastoma

• The over expression of CDK4 causes hyperphosphorylation of RB which causes transformation of normal retinal cell into retinoblastoma. • CDK4 is potent drug target to treat the retinoblastoma. • Compounds 3396 and 960 demonstrated the highest binding efficiency as novel inhibitors of CDK4. • Molecular dynamics simulation results confirm that the RMSD for these compounds remained below 3 Å, with additional binding analysis parameters indicating strong affinity for CDK4. • ADMET analysis revealed that the top compounds are non-toxic and meet the necessary parameters for drug-likeness. Retinoblastoma is a kind of cancer that mostly affects children's eyes, and this study intends to find drugs that can suppress the protein kinase cyclin-dependent kinase 4 (CDK4). CDK4 overexpression leads to the hyper-phosphorylation of RB tumor suppressor protein, which ultimately results in uncontrolled cell division. Aberration of cell cycle regulation, specifically the excessive expression of transcription factors responsible for uncontrolled cell division causes retinoblastoma progression. Hence, we screened 25,000 kinase-targeted small molecules against CDK-4 by Glide in Maestro, the top 11 were chosen based on docking scores, binding modes, chemical variety, and other parameters. We ran molecular dynamics (MD) simulations of top hits found in the docking studies and determined their free binding energy. This helped us to understand their thermodynamic and dynamic properties, as well as confirm the docking results, finally the two most promising ligands (3396 and 960) were obtained. As a result of our research, we have identified promising new compounds for treating retinoblastoma. To validate the possible therapeutic and preventative effects of this ligand, rigorous experimental validation, animal studies as well as clinical trials would be required.