Towards more effective acetylcholinesterase inhibitors: a comprehensive modelling study based on human acetylcholinesterase protein-drug complex

Journal of Biomolecular Structure & Dynamics
Abdulilah Ece

Abstract

Alzheimer's disease is a progressive neurodegenerative disorder and as the exact cause of the disease remains unknown, it still has no cure to date. Due to the fact that, until recently, there has been no crystal structure of human AChE in complex with drugs, researchers have had to use mainly Torpedo californica homologues which were later reported to have significantly different binding sites. In this study, an energy-based pharmacophore model that has the advantages of both ligand- and structure-based approaches was generated using hAChE crystal structures in complex with drugs. This model was validated utilizing several commonly used statistical measures such as the enrichment factor, BEDROC, RIE and AUAC. A huge database consisting of around 7 million compounds with approximately 150,000,000 conformations from 8 vendors was used in virtually screening workflow, in which Lipinski's filter and basic and precise docking algorithms were utilized. A rigorous MM-GBSA binding affinity calculation was also applied to accurately predict relative free energy that produced 361 hits. The selected top ranked 15 compounds were shown to have extra intermolecular interactions with hAChE which is an indication of a more stable complex and ...Continue Reading

References

Jan 1, 1986·British Medical Bulletin·E K Perry
Oct 29, 2000·Acta Crystallographica. Section D, Biological Crystallography·G KrygerJ L Sussman
Mar 29, 2001·Journal of Pharmacological and Toxicological Methods·C A Lipinski
May 31, 2002·Journal of Medicinal Chemistry·Daniel F VeberKenneth D Kopple
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Jun 7, 2005·Proteins·Jason C ColeRobin Taylor
Jun 21, 2006·Chemical Biology & Drug Design·Steven L DixonShashidhar N Rao
Dec 13, 2006·Journal of Medicinal Chemistry·Niu HuangJohn J Irwin
Feb 10, 2007·Journal of Chemical Information and Modeling·Jean-François Truchon, Christopher I Bayly
Sep 28, 2007·Journal of Computer-aided Molecular Design·John C ShelleyMakoto Uchimaya
Dec 14, 2007·Journal of Computer-aided Molecular Design·Ajay N Jain
Jan 25, 2008·Journal of Pharmaceutical Sciences·Carlton A TaftCarlos Henrique Tomich De Paula Da Silva
May 8, 2009·Journal of Computer-aided Molecular Design·Kathryn LovingWoody Sherman
May 13, 2009·Journal of Chemical Information and Modeling·Kirk E HevenerRichard E Lee
Jul 2, 2009·Journal of Computational Chemistry·Giulio RastelliMiriam Sgobba
Sep 19, 2009·Journal of Chemical Information and Modeling·Noeris K SalamWoody Sherman
Oct 7, 2009·Journal of Chemical Information and Modeling·Oranit DrorHaim J Wolfson
Feb 9, 2010·Chemico-biological Interactions·Hay DvirJoel L Sussman
Apr 23, 2010·Journal of Medicinal Chemistry·Eugénie CarlettiFlorian Nachon
Aug 10, 2010·Molecular BioSystems·Alberto Del RioGiuseppe Felice Mangiatordi
Apr 5, 2012·Bioorganic & Medicinal Chemistry Letters·Yao ChenYihua Zhang
Oct 6, 2012·Journal of Medicinal Chemistry·Jonah CheungJude J Height
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
May 9, 2013·Current Topics in Medicinal Chemistry·Rodolpho C Braga, Carolina H Andrade
Jul 16, 2014·Alzheimer's Research & Therapy·Jeffrey L CummingsKate Zhong
Sep 10, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Abdulilah Ece, Boris Pejin
Oct 2, 2015·Nature Reviews. Drug Discovery·Alexandra Flemming
Dec 15, 2015·Journal of Chemical Information and Modeling·Zunnan Huang, Chung F Wong
Jun 17, 2016·Bioinformatics·Sankar Basu, Björn Wallner
Jun 16, 2017·Journal of Biomolecular Structure & Dynamics·Prabu Manoharan, Nanda Ghoshal
Jan 15, 2018·Journal of Molecular Modeling·Nadia Melo BorgesRicardo Gargano
Mar 27, 2018·Journal of Biomolecular Structure & Dynamics·Pravin AmbureKunal Roy
Apr 3, 2018·Journal of Biomolecular Structure & Dynamics·A L PascoiniI Camps
Apr 27, 2018·Journal of Biomolecular Structure & Dynamics·Fereshteh ShiriJahan B Ghasemi
Sep 21, 2018·Journal of Biomolecular Structure & Dynamics·George Nicolae Daniel IonGeorge Mihai Nitulescu

❮ Previous
Next ❯

Citations

Aug 9, 2019·Journal of Biomolecular Structure & Dynamics·Sitrarasu Vijaya Prabhu, Sanjeev Kumar Singh
Jan 31, 2020·Journal of Biomolecular Structure & Dynamics·Shenjiao TangFangfang Wang
Jul 25, 2020·Journal of Biomolecular Structure & Dynamics·Ana Mércia Silva MascarenhasFranco Henrique Andrade Leite

❮ Previous
Next ❯

Software Mentioned

Glide XP
Schrödinger package
MM
QikProp
Schrödinger
GBSA
Maestro
Schrödinger Preparation Wizard
Glide SP

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.