Artificial neural network models driven novel virtual screening workflow for the identification and biological evaluation of BACE1 inhibitors.

Beta-site amyloid-β precursor protein-cleaving enzyme 1 (BACE1) is a transmembrane aspartic protease and has shown potential as a possible therapeutic target for Alzheimer's disease. This aggravating disease involves the aberrant production of β amyloid plaques by BACE1 which catalyzes the rate-limiting step by cleaving the amyloid precursor protein (APP), generating the neurotoxic amyloid β protein that aggregates to form plaques leading to neurodegeneration. Therefore, it is indispensable to inhibit BACE1, thus modulating the APP processing. In this study, we present a workflow that utilizes a multi-stage virtual screening protocol for identifying potential BACE1 inhibitors by employing multiple artificial neural network-based models. Collectively, all the hyperparameter tuned models were assigned a task to virtually screen Maybridge library, thus yielding a consensus of 41 hits. The majority of these hits exhibited optimal pharmacokinetic properties confirmed by high central nervous system multiparameter optimization (CNS-MPO) scores. Further shortlisting of 8 compounds by molecular docking into the active site of BACE1 and their subsequent in-vitro evaluation identified 4 compounds as potent BACE1 inhibitors with IC50 values falling in the range 0.028-0.052 μM and can be further optimized with medicinal chemistry efforts to improve their activity.