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Alzheimer's disease (AD) is one of the most common, progressive neurodegenerative disorders affecting the aged populations. Though various disease pathologies have been suggested for AD, the impairment of the cholinergic system is one of the critical factors for the disease progression. Restoration of the cholinergic transmission through acetylcholinesterase (AChE) inhibitors is a promising disease modifying therapy. Being the first marketed drug for AD, tacrine reversibly inhibits AChE and thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain. However, the atomic level of interactions of tacrine towards human AChE (hAChE) is unknown for years. Hence, in the current study, we report the X-ray structure of hAChE-tacrine complex at 2.85 Å resolution. The conformational heterogeneity of tacrine within the electron density was addressed with the help of molecular mechanics assisted methods and the low-energy ligand configuration is reported, which provides a mechanistic explanation for the high binding affinity of tacrine towards AChE. Additionally, structural comparison of reported hAChE structures sheds light on the conformational selection and induced fit effects of various active site residues upon binding to different ligands and provides insight for future drug design campaigns against AD where AChE is a drug target., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is an obstinate and progressive neurodegenerative disorder, mainly characterized by cognitive decline. Increasing number of AD patients and the lack of promising treatment strategies demands novel therapeutic agents to combat various disease pathologies in AD. Recent progresses in understanding molecular mechanisms in AD helped researchers to streamline the various therapeutic approaches. Inhibiting acetylcholinesterase (AChE) activity has emerged as one of the potential treatment strategies. The present study discusses the identification of two potent AChE inhibitors (ZINC11709541 and ZINC11996936) from ZINC database through conventional in silico approaches and their in vitro validations. These inhibitors have strong preferences towards AChE than butyrylcholinesterase (BChE) and didn't evoke any significant reduction in the cell viability of HEK-293 cells and primary cortical neurons. Furthermore, promising neuroprotective properties has also been displayed against glutamate induced excitotoxicity in primary cortical neurons. The present study proposes two potential drug lead compounds for the treatment of AD, that can be used for further studies and preclinical evaluation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Aβ, which acts as a potential seed for the aggregation of full length Aβ. Preventing the formation of pGlu-Aβ through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC 50  = 34 μM). Systematic molecular docking, MD simulations and X-ray crystallographic analysis provided atomistic details of the binding of Cpd-41 in the active site of sQC. The unique mode of binding and moderate toxicity of Cpd-41 make this molecule an attractive candidate for designing high affinity sQC inhibitors., (Copyright © 2020 Elsevier B.V. All rights reserved.)