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A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations.

ABSTRACT: The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective pharmacological inhibition of CDK4/6 has proven to be beneficial in the treatment of estrogen receptor-positive (ER-positive) breast cancer, particularly improving the progression-free survival of patients. Thus, targeting specific inhibition on CDK4/6 is bound to increase therapeutic efficiency. This study aimed to obtain CDK4/6 inhibitors through a pharmacophore-based virtual screening of the ZINC15 purchasable compound database using the in silico method. The pharmacophore model was designed based on the FDA-approved cdk4/6 inhibitor structures, and molecular docking was performed to further screen the hit compounds obtained. A total of eight compounds were selected based on docking results and interactions with CDK4 and CDK6, using palbociclib as the reference drug. According to the results, the compounds of ZINC585292724 and ZINC585291674 were the best compounds based on free binding energy, as well as hydrogen bond stability, and, therefore, exhibit potential as starting points in the development of CDK4/6 inhibitors.

SUBMITTER: Susanti NMP

PROVIDER: S-EPMC8706085 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The outbreak of novel Coronavirus, an enduring pandemic declared by WHO, has consequences to an alarming ongoing public health menace which has already claimed several million human lives. In addition to numerous vaccinations and medications for mild to moderate COVID-19 infection, lack of promising medication or therapeutic pharmaceuticals remains a serious concern to counter the ongoing coronavirus infections and to hinder its dreadful spread. Global health emergencies have called for urgency for potential drug discovery and time is the biggest constraint apart from the financial and human resources required for the high throughput drug screening. However, computational screening or in-silico approaches appeared to be an effective and faster approach to discover potential molecules without sacrificing the model animals. Accumulated shreds of evidence on computational studies against viral diseases have revealed significance of in-silico drug discovery approaches especially in the time of urgency. The central role of RdRp in SARS-CoV-2 replication makes it promising drug target to curtain on going infection and its spread. The present study aimed to employ E-pharmacophore-based virtual screening to reveal potent inhibitors of RdRp as potential leads to block the viral replication. An energy-optimised pharmacophore model was generated to screen the Enamine REAL DataBase (RDB). Then, ADME/T profiles were determined to validate the pharmacokinetics and pharmacodynamics properties of the hit compounds. Moreover, High Throughput Virtual Screening (HTVS) and molecular docking (SP & XP) were employed to screen the top hits from pharmacophore-based virtual screening and ADME/T screen. The binding free energies of the top hits were calculated by conducting MM-GBSA analysis followed by MD simulations to determine the stability of molecular interactions between top hits and RdRp protein. These virtual investigations revealed six compounds having binding free energies of -57.498, -45.776, -46.248, -35.67, -25.15 and -24.90 kcal/mol respectively as calculated by the MM-GBSA method. The MD simulation studies confirmed the stability of protein ligand complexes, hence, indicating as potent RdRp inhibitors and are promising candidate drugs to be further validated and translated into clinics in future.

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A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations.

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