UNVEILING THE DRUGGABLE HOTSPOTS OF BRSK1: A FRAGMENT-BASED MOLECULAR DOCKING APPROACH FOR DEVELOPING NOVEL INHIBITOR SCAFFOLDS

Abstract

Alzheimer’s disease is a neurodegenerative disease that pose as a significant threat to the existing old age population. The underlying mechanism for the cause of the disease is not yet understood and there has been delay in producing medicinal cure. BRSK1 (Breast tumor kinase 1) is considered to be one of the proteins involved in Amyloid beta (Aβ) aggregation, thus serving as a promising therapeutic target. In this study, we employed a fragment-based molecular docking approach to identify potential druggable hotspots within the BRSK1 binding pocket. By screening a phytochemical library of small molecular fragments, we were able to map the crucial interactions and binding determinants that govern the recognition of BRSK1 by potential inhibitors. Through extensive computational analyses, we identified a set of fragment hits that exhibited favourable binding affinities and complementary binding modes within the target's binding site. These fragment hits were subsequently utilized as starting points for structural elaboration and optimization, leading to the generation of novel inhibitor scaffolds with enhanced potency and selectivity against BRSK1. Results Initial docking result of BRSK1 against IMPPAT library gave 160 were selected as top molecules. After analysing them for their pharmacological properties such as blood-brain barrier (BBB) permeability, GI absorption, hydrogen bonds, solubility and subsequently their ADMET score potential 8 candidates have been selected out of which one compound showed binding to the amino acid at the binding site. This demonstrated to be the best potent inhibitor of BRSK1 hyperphosphorylation. Conclusion The compounds derived from medicinal plants have shown high affinity to be used as a potent inhibitor for BRSK1. The molecular binding between BRSK1 and Ebeinone

showed high affinity score of -9.7 which is desirable drug candidates score in the treatment of AD. Further analysis of the same can be conducted to ratify the computational approach.