Allosteric Modulator Discovery: From Serendipity to Structure-Based Design

Journal of Medicinal Chemistry
Shaoyong LuJian Zhang

Abstract

Allosteric modulators bound to structurally diverse allosteric sites can achieve better pharmacological advantages than orthosteric ligands. The discovery of allosteric modulators, however, has been traditionally serendipitous, owing to the complex nature of allosteric modulation. Recent advances in the understanding of allosteric regulatory mechanisms and remarkable availability of structural data of allosteric proteins and modulators, as well as their complexes, have greatly contributed to the development of various computational approaches to guide the structure-based discovery of allosteric modulators. This Perspective first outlines the evolution of the allosteric concept and describes the advantages and hurdles facing allosteric modulator discovery. The current available computational approaches, together with experimental approaches aiming to highlight allosteric studies, are then highlighted, emphasizing successful examples with their combined applications. We aimed to increase the awareness of the feasibility of the structure-based discovery of allosteric modulators using an integrated computational and experimental paradigm.

References

Jan 1, 1984·European Biophysics Journal : EBJ·A Cooper, D T Dryden
Jul 1, 1999·Protein Science : a Publication of the Protein Society·C J TsaiR Nussinov
Oct 3, 1999·Protein Engineering·B MaR Nussinov
Dec 11, 1999·Cell Biochemistry and Biophysics·S KumarR Nussinov
May 1, 1965·Journal of Molecular Biology·J MONODJ P CHANGEUX
Jan 1, 1961·Cold Spring Harbor Symposia on Quantitative Biology·J MONOD, F JACOB
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Mark E HatleyRama Ranganathan
Mar 17, 2004·The Journal of Biological Chemistry·Anthony A Fodor, Richard W Aldrich
Dec 8, 2004·Current Opinion in Structural Biology·Jeanne A Hardy, James A Wells
Jun 4, 2005·Science·Jean-Pierre Changeux, Stuart J Edelstein
Nov 10, 2005·Proceedings of the National Academy of Sciences of the United States of America·Patrik LundströmMikael Akke
Jan 28, 2006·Cell·Raul MostoslavskyFrederick W Alt
Jan 2, 2007·Proceedings of the National Academy of Sciences of the United States of America·Andrew D FergusonJohann Deisenhofer
Jul 20, 2007·Nature·Kendra King FrederickA Joshua Wand
Oct 3, 2007·Proteins·Rodney HarrisDavid S Goodsell
Mar 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Celestine N ChiPer Jemth
Mar 18, 2008·Current Opinion in Chemical Biology·Jana A LewisCraig W Lindsley
Jun 19, 2008·Protein Science : a Publication of the Protein Society·Qiang Cui, Martin Karplus
Jul 22, 2008·Nature Chemical Biology·Nina M Goodey, Stephen J Benkovic
Aug 19, 2008·Trends in Biochemical Sciences·Aron W Fenton
Oct 18, 2008·Science·Jeeyeon LeeRama Ranganathan
Aug 15, 2009·Structure·Antonio del SolRuth Nussinov
Oct 16, 2009·Proceedings of the National Academy of Sciences of the United States of America·Chad M PetitAndrew L Lee
Nov 6, 2009·Plant Physiology·Susan K BoehleinJon D Stewart
Nov 20, 2009·Nature·Shiou-Ru Tzeng, Charalampos G Kalodimos
Jan 9, 2010·Annual Review of Pharmacology and Toxicology·Jean-Pierre Changeux
Jan 15, 2010·Nature·Jianming ZhangNathanael S Gray
Feb 6, 2010·Science·Vincent J Hilser
Apr 13, 2010·Nature Chemical Biology·Michael S MarlowA Joshua Wand
Jun 4, 2010·Blood·Daniel W SherbenouMichael W Deininger
Aug 24, 2010·Trends in Biochemical Sciences·Ruth I Tennen, Katrin F Chua
Sep 25, 2010·Molecular Systems Biology·Robert G SmockLila M Gierasch
Nov 6, 2010·Nucleic Acids Research·Zhimin HuangJian Zhang
Nov 17, 2010·Pharmacological Reviews·Nicola J Smith, Graeme Milligan
Nov 27, 2010·Current Opinion in Structural Biology·Shiou-Ru Tzeng, Charalampos G Kalodimos
Feb 5, 2011·ACS Chemical Biology·Stephane BetziErnst Schönbrunn
Feb 22, 2011·Current Opinion in Structural Biology·Ron Elber
Apr 26, 2011·Journal of Chemical Information and Modeling·Yaxia YuanLuhua Lai
Sep 20, 2011·Trends in Pharmacological Sciences·Ruth NussinovPeter Csermely
Nov 1, 2011·Nature Biotechnology·Mindy I DavisPatrick P Zarrinkar
Nov 5, 2011·Methods in Molecular Biology·Dennis R LivesayAnthony A Fodor

❮ Previous
Next ❯

Citations

Feb 6, 2020·International Journal of Molecular Sciences·Olivier Sheik AmamuddyOzlem Tastan Bishop
Feb 13, 2020·Natural Product Reports·Marjorie BruderDaniela B B Trivella
May 28, 2019·Cell Communication and Signaling : CCS·Fei LiYu Zhang
Oct 31, 2019·Nucleic Acids Research·Xinyi LiuJian Zhang
Jul 28, 2020·Expert Opinion on Therapeutic Patents·Qiaohong GengQ Ping Dou
Feb 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiaolan ChenNa Zhang
Apr 15, 2020·International Journal of Molecular Sciences·Shuang ZhaoHui-Yu Li
Jan 24, 2020·Frontiers in Chemistry·Zarko GagicKatarina Nikolic
Jan 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Chunqiong LiRugang Zhong
Sep 18, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Francesca CarofiglioOrazio Nicolotti
Nov 17, 2020·Chemical Biology & Drug Design·Rati Kailash Prasad Tripathi, Senthil Raja Ayyannan
Jun 25, 2019·Pharmacology & Therapeutics·Duan NiShaoyong Lu
Feb 15, 2021·Trends in Pharmacological Sciences·Lauren M SloskyLawrence S Barak
Feb 5, 2021·European Journal of Medicinal Chemistry·István LedneczkiZsolt Némethy
Dec 18, 2020·Frontiers in Molecular Biosciences·Eileen K Jaffe
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xinheng HeShaoyong Lu
Sep 2, 2020·European Journal of Medicinal Chemistry·Yuran QiuShaoyong Lu
Apr 2, 2021·Genomics, Proteomics & Bioinformatics·Hammad NaveedMichael L Maitland
Aug 21, 2020·European Journal of Medicinal Chemistry·Yuemin BianXiang-Qun Xie
Apr 20, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Senfeng XiangMeidan Ying
May 5, 2021·The Journal of Chemical Physics·Seyedeh Maryam Salehi, Markus Meuwly
Oct 17, 2020·ACS Medicinal Chemistry Letters·Bingsong HanMaria-Jesus Blanco
Dec 21, 2019·ACS Medicinal Chemistry Letters·Ting RanWen Liu
Sep 4, 2021·Journal of Medicinal Chemistry·Ricardo A M SerafimMatthias Gehringer
Sep 16, 2021·Journal of Chemical Information and Modeling·Ying YangZhiyan Xiao
Oct 5, 2021·Journal of the American Chemical Society·Tianqing Zhang, Bryan Wei
Dec 9, 2021·Journal of Medicinal Chemistry·Jigang FanJian Zhang
Dec 23, 2021·Expert Opinion on Drug Discovery·Ashfaq Ur RehmanJian Zhang

❮ Previous
Next ❯

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

Annual Review of Pharmacology and Toxicology
Lingyan JinGuowei Fang
Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme
Teruki Honma
© 2022 Meta ULC. All rights reserved