Insilico exploration of the potential inhibitory activity of DrugBank compounds against CDK7 kinase using structure-based virtual screening, molecular docking, and dynamics simulation approach

The CDK-activating complex (CAK), which includes CDK7, cyclin H, and the RING-finger protein (MAT1), drives cell cycle advancement via T-loop phosphorylation of cell cycle CDKs. The heterotrimeric CAK complex is a component of TFIIH, a generic transcription factor with dual functions in transcription and cell cycle control. CDK7 facilitates transcription by phosphorylating RNA polymerase II (Pol II) at active gene promoters. The “hallmark of cancer” has been attributed to cell cycle dysregulation, as well as aberrant transcriptions mediated by various pathways found in a variety of malignancies. Furthermore, clinical outcomes show that CDK7 levels are abundantly produced in many types of malignancies, implying that it may play a role in tissue maintenance. As a result, CDK7 is regarded as a malignant therapeutic target. Selective CDK7 inhibitors (CDK7i) have been found to work as anti-cancer medications. Drugs being repurposed for CDK7 kinase treatments is a viable strategy to swiftly uncover powerful therapeutic options for some of the most challenging forms of cancer. All of the DrugBank database chemicals, as well as the CDK7 kinase protein, were prepared, and Maestro (Schrödinger Suite) and GROMACS software suite were used to perform Docking, ADMET, MMGBSA, and MD simulation analyses. After screening the DrugBank molecules against CDK7 kinase, compounds including DB07075, DB07163, DB07025, DB01204, DB03916, DB02943, DB07812, and DB07959 were discovered to fit in the active site of the CDK7 kinase and demonstrate tight interactions. The top three docked compounds were tested, and the MD simulation revealed that they were stable with the target protein at 200 ns. As a result, these chemicals have the potential to be effective CDK7 Kinase inhibitors. As a final result, we present DB07075 (3-(5-[4-(aminomethyl)piperidin-1-yl]methyl-1H-indol-2-yl)-1H-indazole-6-carbonitrile) is a reversible inhibitor because it inactivates an enzyme through non-covalent, reversible interactions that could be a more promising inhibitor of CDK7 kinase by interacting with CDK7 kinase. This novel molecule, DB07075 has met all in silico criteria, necessitating further in vitro and in vivo research, especially in clinical trials.