Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGIu5) X-ray Structures

被引：63

作者：

Christopher, John A. ^{[1
]}

Orgovan, Zoltan ^{[2
]}

Congreve, Miles ^{[1
]}

Dore, Andrew S. ^{[1
]}

Errey, James C. ^{[1
]}

Marshall, Fiona H. ^{[1
]}

Mason, Jonathan S. ^{[1
]}

Okrasa, Krzysztof ^{[1
]}

Rucktooa, Prakash ^{[1
]}

Serrano-Vega, Maria J. ^{[1
]}

Ferenczy, Gyorgy G. ^{[2
]}

Keseru, Gyorgy M. ^{[2
]}

机构：

[1] Heptares Therapeut Ltd, BioPark, Welwyn Garden City AL7 3AX, Herts, England

[2] Hungarian Acad Sci, Res Ctr Nat Sci, Med Chem Res Grp, 2 Magyar Tudosok Korutja, H-1117 Budapest, Hungary

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 01期

关键词：

DRUG DESIGN; DISCOVERY; ANTAGONISTS; POTENT; MGLU(5); TARGET; TRIAL; OPPORTUNITIES; DRUGGABILITY; DERIVATIVES;

D O I：

10.1021/acs.jmedchem.7b01722

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two interesting new X-ray structures of negative allosteric modulator (NAM) ligands for the mGlu(5) receptor, M-MPEP (3) and fenobam (4), are reported. The new structures show how the binding of the ligands induces different receptor water channel conformations to previously published structures. The structure of fenobam, where a urea replaces the acetylenic linker in M-MPEP and mavoglurant, reveals a binding mode where the ligand is rotated by 180 compared to a previously proposed docking model. The need for multiple ligand structures for accurate GPCR structure-based drug design is demonstrated by the different growing vectors identified for the head groups of M-MPEP and mavoglurant and by the unexpected water-mediated receptor interactions of a new chemotype represented by fenobam. The implications of the new structures for ligand design are discussed, with extensive analysis of the energetics of the water networks of both pseudoapo and bound structures providing a new design strategy for allosteric modulators.

引用

页码：207 / 222

页数：16

共 59 条

[1] Towards automated crystallographic structure refinement with phenix.refine [J].

Afonine, Pavel V. ;

Grosse-Kunstleve, Ralf W. ;

Echols, Nathaniel ;

Headd, Jeffrey J. ;

Moriarty, Nigel W. ;

Mustyakimov, Marat ;

Terwilliger, Thomas C. ;

Urzhumtsev, Alexandre ;

Zwart, Peter H. ;

Adams, Paul D. .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2012, 68 :352-367

[2] Synthesis and receptor assay of aromatic-ethynyl-aromatic derivatives with potent mGluR5 antagonist activity [J].

Alagille, D ;

Baldwin, RM ;

Roth, BL ;

Wroblewski, JT ;

Grajkowska, E ;

Tamagnan, GD .

BIOORGANIC & MEDICINAL CHEMISTRY, 2005, 13 (01) :197-209

[3] Structure-based drug design of chromone antagonists of the adenosine A2A receptor [J].

Andrews, Stephen P. ;

Mason, Jonathan S. ;

Hurrell, Edward ;

Congreve, Miles .

MEDCHEMCOMM, 2014, 5 (05) :571-575

[4] Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity [J].

Anighoro, Andrew ;

Graziani, Davide ;

Bettinelli, Ilaria ;

Cilia, Antonio ;

De Toma, Carlo ;

Longhi, Matteo ;

Mangiarotti, Fabio ;

Menegon, Sergio ;

Pirona, Lorenza ;

Poggesi, Elena ;

Riva, Carlo ;

Rastelli, Giulio .

BIOORGANIC & MEDICINAL CHEMISTRY, 2015, 23 (13) :3040-3058

[5]

[Anonymous], 2005, NON TRADITIONAL REF, V11

[6]

Ballesteros J. A., 1995, Methods in Neurosciences, V25, P366, DOI [10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471(05)80049-7]

[7] Discovery of VU0431316: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety [J].

Bates, Brittney S. ;

Rodriguez, Alice L. ;

Felts, Andrew S. ;

Morrison, Ryan D. ;

Venable, Daryl F. ;

Blobaum, Anna L. ;

Byers, Frank W. ;

Lawson, Kera P. ;

Daniels, J. Scott ;

Niswender, Colleen M. ;

Jones, Carrie K. ;

Conn, P. Jeffrey ;

Lindsley, Craig W. ;

Emmitte, Kyle A. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (15) :3307-3314

[8] Structures of mGluRs shed light on the challenges of drug development of allosteric modulators [J].

Bennett, Kirstie A. ;

Dore, Andrew S. ;

Christopher, John A. ;

Weiss, Dahlia R. ;

Marshall, Fiona H. .

CURRENT OPINION IN PHARMACOLOGY, 2015, 20 :1-7

[9]

Bortolato A, 2018, METHODS MOL BIOL, V1705, P207, DOI 10.1007/978-1-4939-7465-8_10

[10] 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

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