Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase

Frontiers in Chemistry
Zhiyang ZhangChaojie Wang

Abstract

Butyrylcholinesterase (BChE) is a non-specific enzyme with clinical pharmacological and toxicological significance, which was a renewed interest as therapeutic target in Alzheimer's disease (AD) nowadays. Here, all-atom molecular dynamics simulations of butyrylcholinesterase with tacrine complex were designed to characterize inhibitor binding modes, strengths, and the hydrogen-bond dependent non-covalent release mechanism. Four possible release channels were identified, and the most favorable channel was determined by random acceleration molecular dynamics molecular dynamics (RAMD MD) simulations. The thermodynamic and dynamic properties as well as the corresponding Detour-forward delivery mechanism were determined according to the classical molecular dynamics (MD) simulations accompanied with umbrella sampling. The free energy barrier of the tacrine release process for the most beneficial pathway is about 10.95 kcal/mol, which is related to the non-covalent interactions from the surrounding residues, revealing the specific binding characteristics in the active site. The residues including Asp70, Ser79, Trp82, Gly116, Thr120, Tyr332, and His438 were identified to play major roles in the stabilization of tacrine in the pocket of...Continue Reading

References

Jul 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·I Grundke-IqbalL I Binder
Nov 10, 1998·Cell Biology and Toxicology·D Lagadic-GossmannA Guillouzo
May 5, 2000·The Cochrane Database of Systematic Reviews·N QizilbashS Szeto
Oct 9, 2001·Mechanisms of Ageing and Development·V N Talesa
Apr 5, 2003·Neurochemical Research·Ezio Giacobini
Dec 4, 2003·Journal of Computational Chemistry·Holger Gohlke, David A Case
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Nov 9, 2005·Proceedings of the National Academy of Sciences of the United States of America·Nigel H GreigDebomoy K Lahiri
Aug 18, 2006·Journal of Alzheimer's Disease : JAD·William K Summers
Jul 20, 2007·The Cochrane Database of Systematic Reviews·N QizilbashS Szeto
May 22, 2009·Journal of Neurochemistry·John Hardy
Jan 29, 2011·BMC Structural Biology·Michał RostkowskiJan H Jensen
Nov 5, 2011·Current Medicinal Chemistry·M BajdaB Malawska
Nov 6, 2012·Journal of Chemical Information and Modeling·Hemant Kumar Srivastava, G Narahari Sastry
Feb 26, 2013·Archives of Pharmacal Research·Preet Anand, Baldev Singh
Aug 10, 2013·The Primary Care Companion to CNS Disorders·Agneta NordbergMonique Somogyi
Oct 18, 2013·Journal of Medicinal Chemistry·Michela RosiniCarlo Melchiorre
Oct 28, 2014·CNS & Neurological Disorders Drug Targets·Gohar MushtaqMohammad A Kamal
Oct 21, 2015·Frontiers in Pharmacology·Xiaojuan SunYan-Dong Wang
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Oct 25, 2016·Future Medicinal Chemistry·M Amélia SantosSílvia Chaves
Nov 24, 2016·European Journal of Medicinal Chemistry·Bilqees SameemAbbas Shafiee
Jan 9, 2017·European Journal of Medicinal Chemistry·Jakub JeřábekMaria Laura Bolognesi
Apr 20, 2017·The Journal of Physical Chemistry Letters·Alessandra MagistratoAndrea Cavalli
Feb 27, 2018·Physical Chemistry Chemical Physics : PCCP·Qiang Shao, Weiliang Zhu
Nov 30, 2018·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Manuela Bartolini, José Marco-Contelles
Dec 15, 2018·Biochimica Et Biophysica Acta. General Subjects·Nai SheChaojie Wang
Mar 10, 2019·European Journal of Medicinal Chemistry·Katarina ChalupovaKamil Kuca

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray

Software Mentioned

AMBER
GBSA
Tacrine
ff14SB
PROPKA
Gaussian03
NAMD
MM
Sybyl
GAFF

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Chemico-biological Interactions
Mushtaq AhmedMaria R C Schetinger
Lancet
K Davis, P Powchik
Drug Safety : an International Journal of Medical Toxicology and Drug Experience
S C Samuels, K L Davis
© 2021 Meta ULC. All rights reserved