Combined Ensemble Docking and Machine Learning in Identification of Therapeutic Agents with Potential Inhibitory Effect on Human CES1

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Eliane BriandOlivier Taboureau

Abstract

The human carboxylesterase 1 (CES1), responsible for the biotransformation of many diverse therapeutic agents, may contribute to the occurrence of adverse drug reactions and therapeutic failure through drug interactions. The present study is designed to address the issue of potential drug interactions resulting from the inhibition of CES1. Based on an ensemble of 10 crystal structures complexed with different ligands and a set of 294 known CES1 ligands, we used docking (Autodock Vina) and machine learning methodologies (LDA, QDA and multilayer perceptron), considering the different energy terms from the scoring function to assess the best combination to enable the identification of CES1 inhibitors. The protocol was then applied on a library of 1114 FDA-approved drugs and eight drugs were selected for in vitro CES1 inhibition. An inhibition effect was observed for diltiazem (IC50 = 13.9 µM). Three others drugs (benztropine, iloprost and treprostinil), exhibited a weak CES1 inhibitory effects with IC50 values of 298.2 µM, 366.8 µM and 391.6 µM respectively. In conclusion, the binding site of CES1 is relatively flexible and can adapt its conformation to different types of ligands. Combining ensemble docking and machine learning ap...Continue Reading

References

May 23, 1998·Annual Review of Pharmacology and Toxicology·T Satoh, M Hosokawa
Dec 18, 2001·Chemical Research in Toxicology·C E WheelockB D Hammock
Apr 23, 2002·Nature Structural Biology·Sompop BencharitMatthew R Redinbo
Dec 3, 2002·Journal of Medicinal Chemistry·Craig E WheelockBruce D Hammock
Apr 8, 2003·Nature Structural Biology·Sompop BencharitMatthew R Redinbo
May 30, 2003·Biochemical Society Transactions·M R RedinboP M Potter
Apr 15, 2004·The Journal of Pharmacology and Experimental Therapeutics·Zejin SunWilliam F Bosron
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Jul 23, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Toshiki TabataTsuyoshi Yokoi
Mar 8, 2005·Drug Discovery Today·Matthew R Redinbo, Philip M Potter
Aug 6, 2005·Journal of Molecular Biology·Christopher D FlemingMatthew R Redinbo
Oct 26, 2005·Chemico-biological Interactions·John E Casida, Gary B Quistad
May 23, 2006·Amino Acids·D-Q WeiK-C Chou
Aug 22, 2006·Chemico-biological Interactions·Tetsuo Satoh, Masakiyo Hosokawa
Sep 12, 2006·Journal of Molecular Biology·Sompop BencharitMatthew R Redinbo
Mar 24, 2007·Journal of Medicinal Chemistry·Janice L HyattPhilip M Potter
Apr 3, 2007·Bioorganic & Medicinal Chemistry·Latorya D HicksPhilip M Potter
Oct 24, 2007·Journal of Chemical Information and Modeling·Gabriela BarreiroWilliam L Jorgensen
Jan 1, 2008·Biological Chemistry·Timothy M StreitMatthew K Ross
Jan 16, 2008·Journal of Medicinal Chemistry·Irina G TikhonovaMarvin C Gershengorn
Feb 29, 2008·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Masakiyo Hosokawa
Sep 3, 2009·Genome Biology·Nicholas P TatonettiRuss B Altman
Sep 8, 2009·Neuropharmacology·Zsofia NemodaMaria Sasvari-Szekely
May 19, 2010·Nucleic Acids Research·Peter SchmidtkePierre Tufféry
Sep 3, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tatsuki FukamiTsuyoshi Yokoi
Oct 12, 2010·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Roger S HolmesLois J Maltais
Oct 11, 2011·Journal of Cheminformatics·Noel M O'BoyleGeoffrey R Hutchison
Mar 24, 2012·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Harry M GreenblattJoel L Sussman
Jan 1, 2010·Journal of Pest Science·Shana V StoddardRandy M Wadkins
Oct 22, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ragnar ThomsenUNKNOWN INDICES Consortium
Nov 10, 2013·Nucleic Acids Research·Vivian LawDavid S Wishart
Apr 23, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mai ShimizuTsuyoshi Yokoi
Feb 11, 2015·Journal of Computer-aided Molecular Design·Marc C Deller, Bernhard Rupp
Jun 20, 2015·Nature Reviews. Drug Discovery·Michael J WaringAlex Weir
Sep 29, 2015·Expert Opinion on Drug Discovery·Dinler A AntunesLydia E Kavraki

❮ Previous
Next ❯

Citations

Dec 25, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Lucy Her, Hao-Jie Zhu

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray
in-silico techniques

Software Mentioned

TensorFlow
AMBER
Autodock Tools
Learn
SciKit
UCSF Chimera
fpocket
Chembl
OpenBabel
GraphPad

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.

© 2021 Meta ULC. All rights reserved