A Method for Rapid Screening of Anilide-Containing AMPK Modulators Based on Computational Docking and Biological Validation

Frontiers in Pharmacology
Simon W F MokVincent K W Wong

Abstract

Adenosine 5'-monophsphate-activated protein kinase (AMPK) is a crucial energy sensor for maintaining cellular homeostasis. Targeting AMPK may provide an alternative approach in treatment of various diseases like cancer, diabetes, and neurodegenerations. Accordingly, novel AMPK activators are frequently identified from natural products in recent years. However, most of such AMPK activators are interacting with AMPK in an indirect manner, which may cause off-target effects. Therefore, the search of novel direct AMPK modulators is inevitable and effective screening methods are needed. In this report, a rapid and straightforward method combining the use of in silico and in vitro techniques was established for selecting and categorizing huge amount of compounds from chemical library for targeting AMPK modulators. A new class of direct AMPK modulator have been discovered which are anilides or anilide-like compounds. In total 1,360,000 compounds were virtually screened and 17 compounds were selected after biological assays. Lipinski's rule of five assessment suggested that, 13 out of the 17 compounds are demonstrating optimal bioavailability. Proton acceptors constituting the structure of these compounds and hydrogen bonds with AMPK i...Continue Reading

References

Jan 1, 1992·The Biochemical Journal·M F VincentG Van den Berghe
Oct 1, 1991·Diabetes·M F VincentG Van den Berghe
Oct 30, 1985·Biochemical and Biophysical Research Communications·A FerrerF G Hegardt
Jan 12, 1996·The Journal of Biological Chemistry·D StapletonB E Kemp
Jul 6, 2000·British Journal of Pharmacology·J Zheng, V D Ramirez
Jun 27, 2003·Current Opinion in Chemical Biology·Adam GolebiowskiDavid E Portlock
Dec 17, 2004·Nature·Brian K Shoichet
Jul 15, 2006·Nature Biotechnology·Gaia V PaoliniAndrew L Hopkins
Sep 1, 2006·The Journal of Biological Chemistry·Marianne SuterDietbert Neumann
Oct 14, 2006·The Journal of Physiology·J B Birk, J F P Wojtaszewski
Feb 9, 2007·Nature Biotechnology·Michael J KeiserBrian K Shoichet
Nov 24, 2007·Current Opinion in Biotechnology·Ming-Qiang Zhang, Barrie Wilkinson
Jul 22, 2008·Nature Chemical Biology·Adrian Whitty
Sep 18, 2008·International Journal of Obesity : Journal of the International Association for the Study of Obesity·F P Kuhajda
Mar 10, 2010·Current Drug Targets·Marcelo Zaldini HernandesAna Cristina Lima Leite
Jul 6, 2010·Drug Discovery Today·Alejandro MerinoDolores J Cahill
Feb 18, 2011·The EMBO Journal·D Grahame Hardie
Mar 25, 2011·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Antero SalminenKai Kaarniranta
Apr 21, 2012·Science·Simon A HawleyD Grahame Hardie
Nov 10, 2012·Expert Opinion on Therapeutic Patents·Fabrizio Giordanetto, David Karis
Dec 20, 2013·Nature Communications·Bing XiaoSteven J Gamblin
Jan 2, 2014·Pharmacological Reviews·Gregory SliwoskiEdward W Lowe
Feb 6, 2014·EMBO Molecular Medicine·Giorgia ZadraMassimo Loda
Dec 9, 2010·ACS Medicinal Chemistry Letters·Jorge E Gómez-GalenoMark D Erion
Jul 2, 2014·Scientific Reports·Betty Yuen Kwan LawVincent Kam Wai Wong
Jan 27, 2016·Oncotarget·Betty Yuen Kwan LawVincent Kam Wai Wong
Mar 2, 2016·Journal of Health Economics·Joseph A DiMasiRonald W Hansen
Apr 2, 2016·Experimental & Molecular Medicine·Joungmok KimJoohun Ha
Jun 26, 2017·Trends in Endocrinology and Metabolism : TEM·Emily A DayGregory R Steinberg
Jul 4, 2017·Frontiers in Pharmacology·Betty Y K LawVincent K W Wong

❮ Previous
Next ❯

Methods Mentioned

BETA
Fluorescence Imaging
fluorescence microscopy
Assay
protein assay
electrophoresis
fluorescence cell imaging

Software Mentioned

OPLS
Ligprep
Protein Preparation Wizard
Schrödinger
Advanced Chemistry Development ( ACD / Labs )
Chemdiv
Glide
Epik

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.