Zhang KYJ

References (4)

Title : Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery - Dileep_2022_Int.J.Biol.Macromol_210_172
Author(s) : Dileep KV , Ihara K , Mishima-Tsumagari C , Kukimoto-Niino M , Yonemochi M , Hanada K , Shirouzu M , Zhang KYJ
Ref : Int J Biol Macromol , 210 :172 , 2022
Abstract : 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 A 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.
ESTHER : Dileep_2022_Int.J.Biol.Macromol_210_172
PubMedSearch : Dileep_2022_Int.J.Biol.Macromol_210_172
PubMedID: 35526766
Gene_locus related to this paper: human-ACHE

Title : Chemical similarity assisted search for acetylcholinesterase inhibitors: Molecular modeling and evaluation of their neuroprotective properties - Remya_2021_Int.J.Biol.Macromol__
Author(s) : Remya C , Dileep KV , Variyar EJ , Zhang KYJ , Omkumar RV , Sadasivan C
Ref : Int J Biol Macromol , : , 2021
Abstract : 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.
ESTHER : Remya_2021_Int.J.Biol.Macromol__
PubMedSearch : Remya_2021_Int.J.Biol.Macromol__
PubMedID: 33497692

Title : Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation - Remya_2021_Comput.Struct.Biotechnol.J_19_4517
Author(s) : Remya C , Dileep KV , Koti Reddy E , Mantosh K , Lakshmi K , Sarah Jacob R , Sajith AM , Jayadevi Variyar E , Anwar S , Zhang KYJ , Sadasivan C , Omkumar RV
Ref : Comput Struct Biotechnol J , 19 :4517 , 2021
Abstract : The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimer's disease (AD). Tacrine, a potent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepatotoxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed in silico structure-based modifications on tacrine, chemical synthesis of the derivatives and in vitro validation of their activities. Nineteen such derivatives showed inhibition with IC(50) values in the range of 18.53 +/- 2.09 - 184.09 +/- 19.23 nM against AChE and 0.27 +/- 0.05 - 38.84 +/- 9.64 microM against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited in vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activitiy against butyrylcholinesterase. MTDL-201 was also devoid of hepatotoxicity in vivo. Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs among which 201 appears to be a potential candidate for immediate preclinical evaluations.
ESTHER : Remya_2021_Comput.Struct.Biotechnol.J_19_4517
PubMedSearch : Remya_2021_Comput.Struct.Biotechnol.J_19_4517
PubMedID: 34471497

Title : Identification of 1,2,4-triazolylthioethanone Scaffold for the Design of New Acetylcholinesterase Inhibitors - Fatiha_2021_Mol.Inform__
Author(s) : Fatiha Muhammad E , Kumar A , Wahab HA , Zhang KYJ
Ref : Mol Inform , : , 2021
Abstract : Acetylcholinesterase (AChE) inhibitors are the most effective drugs for Alzheimer's disease treatment. However, considering the potential and failure rates of AChE inhibitors, chemical scaffolds targeting cholinesterase specifically are still very limited. Herein, we report a new class of AChE inhibitors identified by employing a virtual screening approach that combines shape similarity with molecular docking calculations. Virtual screening followed by the evaluation of AChE inhibitory activity allowed us to identify 1,2,4-triazolylthioethanones as a novel class of AChE inhibitors. Thirteen compounds with 1,2,4-triazolylthiothanone core and IC(50) values in the range of 0.15+/-0.07 to 3.32+/-0.92microM have been reported here. Our findings shed light into a class of AChE inhibitors that could be useful starting point for the development of novel therapeutics to tackle Alzheimer's disease.
ESTHER : Fatiha_2021_Mol.Inform__
PubMedSearch : Fatiha_2021_Mol.Inform__
PubMedID: 34060234