Metal based donepezil analogues designed to inhibit human acetylcholinesterase for Alzheimer's disease

PloS One
Md JunaidMohammad A Halim

Abstract

Among neurodegenerative disorders, Alzheimer's disease (AD) is one of the most common disorders showing slow progressive cognitive decline. Targeting acetylcholinesterase (AChE) is one of the major strategies for AD therapeutics, as cholinergic pathways in the cerebral cortex and basal forebrain are compromised. Herein, we report the design of some copper and other metal based donepezil derivatives, employing density functional theory (DFT). All designed compounds are optimized at the B3LYP/SDD level of theory. Dipole moments, electronic energie, enthalpies, Gibbs free energies, and HOMO-LUMO gaps of these modified compounds are also investigated in the subsequent analysis. The molecules were then subjected to molecular docking analysis with AChE to study the molecular interactions broadly. Ensemble based docking and molecular dynamics (MD) simulations of the best candidates were also performed. Docking and MD simulation reveal that modified drugs are more potent than unmodified donepezil, where Trp86, Tyr337, Phe330 residues play some important roles in drug-receptor interactions. According to ensemble based docking, D9 shows greater binding affinity compared to the parent in most conformations obtained from protein data bank ...Continue Reading

References

Jul 30, 1982·Science·R T BartusA S Lippa
Jul 25, 1998·The Journal of Biological Chemistry·A OrdentlichA Shafferman
Sep 15, 1988·Physical Review A: General Physics·A D Becke
Oct 16, 1999·The Journal of Biological Chemistry·Y BourneP Marchot
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Oct 29, 2000·Journal of Medicinal Chemistry·W J EganJ J Baldwin
Jul 23, 2003·Journal of Chemical Information and Computer Sciences·Roberta G Susnow, Steven L Dixon
Feb 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·Yves BournePascale Marchot
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Jan 27, 2006·Dalton Transactions : an International Journal of Inorganic Chemistry·Katherine H Thompson, Chris Orvig
Nov 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·R G Pearson
Jul 1, 2008·Chemico-biological Interactions·Israel Silman, Joel L Sussman
Oct 16, 2008·Current Medicinal Chemistry·Christian G HartingerBernhard K Keppler
Mar 5, 2010·International Journal of Sports Medicine·K NakajimaS Taniguchi
Mar 27, 2010·Current Pharmaceutical Design·Michael FrezzaQ Ping Dou
Jan 20, 2012·Bioorganic & Medicinal Chemistry·Preet AnandNirmal Singh
Oct 6, 2012·Journal of Medicinal Chemistry·Jonah CheungJude J Height
Jun 12, 2013·Lancet·Kit Yee ChanUNKNOWN Global Health Epidemiology Reference Group (GHERG)
Jan 25, 2014·Chemical Reviews·Katja Dralle Mjos, Chris Orvig
Feb 25, 2015·Journal of Pharmacy & Bioallied Sciences·Gauresh SomaniSadhana Sathaye
Mar 31, 2017·Advances and Applications in Bioinformatics and Chemistry : AABC·Raju DashSm Zahid Hosen

❮ Previous
Next ❯

Citations

Oct 14, 2020·Journal of Biomolecular Structure & Dynamics·Archi Sundar PaulMohammad A Halim
Dec 24, 2020·Journal of Biomolecular Structure & Dynamics·Rumana MahtarinMohammad A Halim

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray

Software Mentioned

AutodockVina
AutoDock Tools ( ADT )
Autodock Vina
GROMOS
admetSAR
MGL
NAMD
Swiss
PDB Viewer
CHARMM

Related Concepts

Related Feeds

Basal Forebrain- Circuits

Basal forebrain is a region in the brain important for production of acetylcholine and is the major cholinergic output of the CNS. Discover the latest research on circuits in the basal forebrain here.