Hybrid Molecules for Dual Enzyme Inhibition in Alzheimer’s Disease

Abstract

Alzheimer disease (AD) is a multi-factorial neurodegenerative disorder that appears in cognitive decline with a progressive memory loss which is mostly influenced by the pathological benchmarks which include amyloid-beta plaques and cholinergic deficiencies. The given paper describes the logic-based design, synthesis, and biological testing of new hybrid molecules directed against two enzymes that play a role in AD: acetylcholinesterase (AChE) and beta-secretase (BACE-1). Twelve hybrid molecules were designed by structure-based drug design (SBDD) and investigated through in silico docking, ADMET profiling and in vitro enzyme inhibition analyses. Among these, HM-07 was found to be the strongest dual inhibitor under the study, with the docking scores of -8.9 kcal/mol (AChE) and -8.4 kcal/mol (BACE-1) and IC 50 of 0.41 um and 0.56 um respectively. ADMET analysis showed that it has a great drug-likeness and blood-brain barrier (BBB) permeability along with oral bioavailability. Computational modeling displayed high predictivity with respect to biological activity, showing strong inverse correlation (r = =0.86) between docking affinity and biological activity. The results imply that HM-07 is a good lead drug development that can be used in developing multitarget therapeutics in the treatment of Alzheimer disease.