IN SILICO SCREENING OF POTENTIAL THERAPEUTIC MOLECULE RESCUE FROM ALZHEIMER’S DISEASE TARGETING CDK7

Abstract

Evidence suggests that cell cycle activation plays a role in the pathophysiology of neurodegenerative diseases. Alzheimer's disease is a progressive, terminal neurodegenerative disease that affects memory and other important mental functions. Intracellular deposition of Tau protein, a hyperphosphorylated form of a microtubule-associated protein, and extracellular aggregation of Amyloid Beta protein, which manifest as neurofibrillary tangles (NFT) and senile plaques, respectively, characterise this condition. In recent years, however, several studies have concluded that cell cycle re-entry is one of the key causes of neuronal death in the pathogenesis of Alzheimer's disease. The eukaryotic cell cycle is well-coordinated machinery that performs critical functions in cell replenishment, such as DNA replication, cell creation, repair, and the birth of new daughter cells from the mother cell. The complex interplay between the levels of various cyclins and cyclin-dependent kinases (CDKs) at different checkpoints is needed for cell cycle synchronisation. CDKIs (cyclin-dependent kinase inhibitors) prevent cyclin degradation and CDK inactivation. Different external and internal factors regulate them differently, and they have different tissue expression and developmental functions. The checkpoints ensure that the previous step is completed correctly before the start of the new cell cycle phase, and they protect against the transfer of defects to the daughter cells. Initially 22 molecules were screened at 75% similarity with CAPE from ChEMBL database. The assessment of drug likeness feature using Lipinski Rule of 5 of these molecules was done using SwissADME. 16 molecules exhibited drug-like characteristics. These 16 molecules were filtered on the basis of their ADME properties and BBB permeability using tools such as pkCSM and cbligand, herein 8 molecules were shortlisted. These 8 compounds were subjected to molecular docking with human CDK7 protein, and lead compounds were screened on the basis of docking scores and interacting residues. A series of in silico experiments were used for virtual screening and ligand-based drug discovery, and then it was calculated that Compound 9(ChEMBL3976811), compound 6 (ChEMBL3597111) and Compound8 (ChEMBL3958339) can act as lead compound against CDK7 protein and can be developed as a therapeutic solution for AD. Due to the development of more selective and potent ATP-competitive CDK inhibitors, CDK inhibitors appear to be on the verge of having a clinical impact. This avenue is likely to yield new and effective medicines for the treatment of cancer and other neurodegenerative diseases. These new methods for recognising CDK inhibitors may be used to create non-ATP- competitive agents that target CDK4, CDK5, and other CDKs that have been recognised as important therapeutic targets in Alzheimer's disease treatment.