Identification of Novel CDK 4/6 Inhibitors by High-throughput Virtual Screening

Background:: CDK4/6 plays a crucial role in regulating cell proliferation, and inhibiting this kinase can effectively prevent the initiation of cell growth and division. However, current FDAapproved CDK4/6 inhibitors have limitations such as poor bioavailability, adverse effects, high cost, and limited accessibility. Thus, this research aimed to discover novel CDK4/6 inhibitors to overcome the challenges associated with FDA-approved inhibitors. Methods:: To identify potential CDK4/6 inhibitors, we have performed structure-based virtual screening. Chem-space and Mcule databases have been screened, followed by a series of filtering steps. These steps included assessing drug-likeness, PAINS alert, synthetic accessibility scores, ADMET properties, consensus molecular docking, and performing molecular dynamics simulations. Results:: Four new compounds (CSC089414133, CSC091186116, CSC096023304, CSC101755872) have been identified as potential CDK4/6 inhibitors. These compounds exhibited strong binding affinity with CDK4/6, possessed drug-like features, showed no PAINS alert, had a low synthetic accessibility score, demonstrated effective ADMET properties, were non-toxic, and exhibited high stability. Conclusion:: Inhibiting CDK4/6 with the identified compounds may lead to reduced cell proliferation and the promotion of cancer cell death. result: Four compounds (CSC089414133, CSC091186116, CSC096023304, CSC101755872) were identified as potential CDK4/6 inhibitors. These compounds exhibited strong binding affinity at the active site of CDK4/6, possessed drug-like features, showed no PAINS alert, had a low synthetic accessibility score, demonstrated effective ADMET properties, were non-toxic, and exhibited high stability.