Design and Selection of Novel Kinase Inhibitors Implicated in Alzheimer’s Disease by High Throughput Virtual Screening

Abstract

CDK5 (cyclin dependent kinase 5) is a promising target for treating a variety of neurodegenerative illnesses. The discovery of effective and selective CDK5 inhibitors that engage the polar side chains of the ATP-binding pocket as well as establish specific hydrogen bonds with the kinase has made significant progress. To find novel prospective CDK5 inhibitors with improved effectiveness, ADME characteristics, and a large margin of safety. High throughput virtual screening employing flexible docking was used to screen 2,50,000 compounds from the Specs database against the CDK5 crystal structure (PDB ID: 1UNL). The docking simulation was performed using HTVS first, then SP, and finally XP. The interaction pattern to the receptor with fresh lead candidates has been found and selected based on the GLIDE docking score. The lead moiety in the co-crystallized roscovitine with CDK5 complex retains critical H-bonding patterns while also introducing hydrophobic interactions with Ile10 and Leu133. Selected hits demonstrate hydrophobic interactions with Asn 144, Gly 13, and Ala143 within the ATP cleft in a comparable way to reference compounds (Roscovitine). The lead compound's binding pattern revealed by GLIDE docking experiments demonstrated that molecules bind to the kinase's well-conserved catalytic pocket.