Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs

被引：98

作者：

Congreve, Miles ^{[1
]}

Oswald, Christine ^{[1
]}

Marshall, Fiona H. ^{[1
]}

机构：

[1] Heptares Therapeut Ltd, Welwyn Garden City, Herts, England

来源：

TRENDS IN PHARMACOLOGICAL SCIENCES | 2017年 / 38卷 / 09期

关键词：

PROTEIN-COUPLED RECEPTORS; MUSCARINIC ACETYLCHOLINE-RECEPTOR; CRYSTAL-STRUCTURE; BINDING-SITE; MOLECULAR-MECHANISMS; HIV ENTRY; ANTAGONISTS; DISCOVERY; ACTIVATION; RESOLUTION;

D O I：

10.1016/j.tips.2017.05.010

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Structural insights have been revealed from X-ray co-complexes of a range of G protein-coupled receptors (GPCRs) and their allosteric ligands. The understanding of how small molecules can modulate the function of this important class of receptors by binding to a diverse range of pockets on and inside the proteins has had a profound impact on the structure-based drug design (SBDD) of new classes of therapeutic agents. The types of allosteric pockets and the mode of modulation as well as the advantages and disadvantages of targeting allosteric pockets (as opposed to the natural orthosteric site) are considered in the context of these new structural findings.

引用

页码：837 / 847

页数：11

共 51 条

[1]

Molecular Determinants of Allosteric Modulation at the M1 Muscarinic Acetylcholine Receptor [J].

Abdul-Ridha, Alaa ;

Lopez, Laura ;

Keov, Peter ;

Thal, David M. ;

Mistry, Shailesh N. ;

Sexton, Patrick M. ;

Lane, J. Robert ;

Canals, Meritxell ;

Christopoulos, Arthur .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (09) :6067-6079

[2]

Prediction of allosteric sites and mediating interactions through bond-to-bond propensities [J].

Amor, B. R. C. ;

Schaub, M. T. ;

Yaliraki, S. N. ;

Barahona, M. .

NATURE COMMUNICATIONS, 2016, 7

[3]

An intracellular allosteric site for a specific class of antagonists of the CC chemokine G protein-coupled receptors CCR4 and CCR5 [J].

Andrews, Glen ;

Jones, Carolyn ;

Wreggett, Keith A. .

MOLECULAR PHARMACOLOGY, 2008, 73 (03) :855-867

[4]

Decoding the Role of Water Dynamics in Ligand-Protein Unbinding: CRF1R as a Test Case [J].

Bortolato, Andrea ;

Deflorian, Francesca ;

Weiss, Dahlia R. ;

Mason, Jonathan S. .

JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2015, 55 (09) :1857-1866

[5]

Structural basis of Smoothened regulation by its extracellular domains [J].

Byrne, Eamon F. X. ;

Sircar, Ria ;

Miller, Paul S. ;

Hedger, George ;

Luchetti, Giovanni ;

Nachtergaele, Sigrid ;

Tully, Mark D. ;

Mydock-McGrane, Laurel ;

Covey, Douglas F. ;

Rambo, Robert P. ;

Sansom, Mark S. P. ;

Newstead, Simon ;

Rohatgi, Rajat ;

Siebold, Christian .

NATURE, 2016, 535 (7613) :517-522

[6]

Structure of the adenosine A2A receptor bound to an engineered G protein [J].

Carpenter, Byron ;

Nehme, Rony ;

Warne, Tony ;

Leslie, Andrew G. W. ;

Tate, Christopher G. .

NATURE, 2016, 536 (7614) :104-+

[7]

Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation [J].

Changeux, Jean-Pierre ;

Christopoulos, Arthur .

CELL, 2016, 166 (05) :1084-1102

[8]

Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile) [J].

Christopher, John A. ;

Aves, Sarah J. ;

Bennett, Kirstie A. ;

Dore, Andrew S. ;

Errey, James C. ;

Jazayeri, Ali ;

Marshall, Fiona H. ;

Okrasa, Krzysztof ;

Serrano-Vega, Maria J. ;

Tehan, Benjamin G. ;

Wiggin, Giselle R. ;

Congreve, Miles .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (16) :6653-6664

[9]

Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain [J].

Dore, Andrew S. ;

Okrasa, Krzysztof ;

Patel, Jayesh C. ;

Serrano-Vega, Maria ;

Bennett, Kirstie ;

Cooke, Robert M. ;

Errey, James C. ;

Jazayeri, Ali ;

Khan, Samir ;

Tehan, Ben ;

Weir, Malcolm ;

Wiggin, Giselle R. ;

Marshall, Fiona H. .

NATURE, 2014, 511 (7511) :557-+

[10]

Orthosteric versus allosteric GPCR activation: The great challenge of group-III mGluRs [J].

Flor, Peter J. ;

Acher, Francine C. .

BIOCHEMICAL PHARMACOLOGY, 2012, 84 (04) :414-424

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