Structure-based development of a subtype-selective orexin 1 receptor antagonist

Hellmann, Jan; Drabek, Matthäus; Yin, Jie; Gunera, Jakub; Pröll, Theresa; Kraus, Frank; Langmead, Christopher J.; Hübner, Harald; Weikert, Dorothee; Kolb, Peter; Rosenbaum, Daniel M.; Gmeiner, Peter

doi:10.1073/pnas.2002704117

Title: Structure-based development of a subtype-selective orexin 1 receptor antagonist

Abstract

Orexin receptors belong to the superfamily of G-protein–coupled receptors (GPCRs) which represent the largest class of drug targets in humans. Despite the recent progress in structural biology, the development of subtype-selective orexin receptor and GPCR ligands in general remains challenging, due to the high sequence similarity among individual receptor subtypes. However, subtype-selective molecules are key to discerning the individual contributions of receptor subtypes to (patho-)physiology. Starting from the clinically used, non–subtype-selective orexin receptor antagonist suvorexant, we demonstrate how docking, crystallography, medicinal chemistry, and in vitro pharmacology can be combined to exploit single amino acid sequence differences for the discovery of subtype-selective probes. Such compounds will help to better understand orexin receptor pharmacology and develop promising drug candidates.

Authors:

^[1];

^[2]; Yin, Jie ^[3]; Gunera, Jakub ^[2]; Pröll, Theresa ^[1];

^[1]; Langmead, Christopher J. ^[4];

^[1];

^[2];

^[1]

Friedrich-Alexander-Univ. Erlangen-Nürnberg (Germany)
Philipps Univ., Marburg (Germany)
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Monash Univ., Melbourne, VIC (Australia)

Publication Date:: Tue Jul 28 00:00:00 EDT 2020

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Org.:: USDOE Office of Science (SC)

Contributing Org.:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

OSTI Identifier:: 1671133

Resource Type:: Accepted Manuscript

Journal Name:: Proceedings of the National Academy of Sciences of the United States of America

Additional Journal Information:: Journal Volume: 117; Journal Issue: 30; Journal ID: ISSN 0027-8424

Publisher:: National Academy of Sciences

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Hellmann, Jan, Drabek, Matthäus, Yin, Jie, Gunera, Jakub, Pröll, Theresa, Kraus, Frank, Langmead, Christopher J., Hübner, Harald, Weikert, Dorothee, Kolb, Peter, Rosenbaum, Daniel M., and Gmeiner, Peter. Structure-based development of a subtype-selective orexin 1 receptor antagonist.  United States: N. p., 2020. 
Web.  doi:10.1073/pnas.2002704117.

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                    Hellmann, Jan, Drabek, Matthäus, Yin, Jie, Gunera, Jakub, Pröll, Theresa, Kraus, Frank, Langmead, Christopher J., Hübner, Harald, Weikert, Dorothee, Kolb, Peter, Rosenbaum, Daniel M., & Gmeiner, Peter. Structure-based development of a subtype-selective orexin 1 receptor antagonist.  United States.  https://doi.org/10.1073/pnas.2002704117

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                    Hellmann, Jan, Drabek, Matthäus, Yin, Jie, Gunera, Jakub, Pröll, Theresa, Kraus, Frank, Langmead, Christopher J., Hübner, Harald, Weikert, Dorothee, Kolb, Peter, Rosenbaum, Daniel M., and Gmeiner, Peter. Tue .  
"Structure-based development of a subtype-selective orexin 1 receptor antagonist".  United States.  https://doi.org/10.1073/pnas.2002704117.  https://www.osti.gov/servlets/purl/1671133.

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@article{osti_1671133,

  title        = {Structure-based development of a subtype-selective orexin 1 receptor antagonist},

  author       = {Hellmann, Jan and Drabek, Matthäus and Yin, Jie and Gunera, Jakub and Pröll, Theresa and Kraus, Frank and Langmead, Christopher J. and Hübner, Harald and Weikert, Dorothee and Kolb, Peter and Rosenbaum, Daniel M. and Gmeiner, Peter},

  abstractNote = {Orexin receptors belong to the superfamily of G-protein–coupled receptors (GPCRs) which represent the largest class of drug targets in humans. Despite the recent progress in structural biology, the development of subtype-selective orexin receptor and GPCR ligands in general remains challenging, due to the high sequence similarity among individual receptor subtypes. However, subtype-selective molecules are key to discerning the individual contributions of receptor subtypes to (patho-)physiology. Starting from the clinically used, non–subtype-selective orexin receptor antagonist suvorexant, we demonstrate how docking, crystallography, medicinal chemistry, and in vitro pharmacology can be combined to exploit single amino acid sequence differences for the discovery of subtype-selective probes. Such compounds will help to better understand orexin receptor pharmacology and develop promising drug candidates.},

  doi          = {10.1073/pnas.2002704117},

  journal      = {Proceedings of the National Academy of Sciences of the United States of America},

  number       = 30,

  volume       = 117,

  place        = {United States},

  year         = {Tue Jul 28 00:00:00 EDT 2020},

  month        = {Tue Jul 28 00:00:00 EDT 2020}

}

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Title: Structure-based development of a subtype-selective orexin 1 receptor antagonist

Abstract

Citation Formats

The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity journal, January 1998

Selective orexin receptor antagonists journal, September 2013

Current Phase II investigational therapies for insomnia journal, October 2014

A review of the role of orexin system in pain modulation journal, June 2017

Reduced Number of Hypocretin Neurons in Human Narcolepsy journal, September 2000

Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET journal, July 2016

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468 journal, June 2017

Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis journal, December 2019

d-myo-Inositol 1-phosphate as a surrogate of d-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation journal, November 2006

Structure-based discovery of opioid analgesics with reduced side effects journal, August 2016

F13. Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of the Selective Orexin-1 Receptor Antagonist JNJ-61393215: Results From the First-In-Human and Multiple Ascending Dose Studies journal, May 2019

The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene journal, August 1999

Label-Free Kinetics: Exploiting Functional Hemi-Equilibrium to Derive Rate Constants for Muscarinic Receptor Antagonists journal, August 2015

Determining the Potency and Molecular Mechanism of Action of Insurmountable Antagonists journal, July 2006

Discovery and Characterization of ACT-335827, an Orally Available, Brain Penetrant Orexin Receptor Type 1 Selective Antagonist journal, April 2013

Probing the activation-promoted structural rearrangements in preassembled receptor–G protein complexes journal, August 2006

Differential expression of orexin receptors 1 and 2 in the rat brain journal, January 2001

The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor journal, September 2015

FRED and HYBRID docking performance on standardized datasets journal, June 2012

The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness journal, February 2007

Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior journal, February 1998

Therapeutics development for addiction: Orexin-1 receptor antagonists journal, March 2020

Lemborexant: First Approval journal, February 2020

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach journal, July 2016

Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs journal, September 2015

Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors journal, March 2016

Role of orexin receptors in obesity: from cellular to behavioral evidence journal, March 2012

Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists journal, November 2018

Distribution of orexin receptor mRNA in the rat brain journal, October 1998

Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia journal, September 2015

Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands: Binding kinetics contrast functional antagonism journal, December 2013

Trends in GPCR drug discovery: new agents, targets and indications journal, October 2017

Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs journal, January 2014

Orexin/hypocretin receptor signalling cascades: Orexin receptor signalling cascades journal, December 2013

In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist journal, May 2017

D 4 dopamine receptor high-resolution structures enable the discovery of selective agonists journal, October 2017

Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database journal, March 2010

Repeated orexin 1 receptor antagonism effects on cocaine seeking in rats journal, December 2012

Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant journal, December 2014

Crystallizing membrane proteins using lipidic mesophases journal, April 2009

Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists journal, January 2015

The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases journal, June 2018

A role for lateral hypothalamic orexin neurons in reward seeking journal, August 2005

Multiplexing of Multicolor Bioluminescence Resonance Energy Transfer journal, December 2010

Binding-Site Compatible Fragment Growing Applied to the Design of β 2 -Adrenergic Receptor Ligands journal, January 2018

FRED Pose Prediction and Virtual Screening Accuracy journal, February 2011

The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity
journal, January 1998

Selective orexin receptor antagonists
journal, September 2013

Current Phase II investigational therapies for insomnia
journal, October 2014

A review of the role of orexin system in pain modulation
journal, June 2017

Reduced Number of Hypocretin Neurons in Human Narcolepsy
journal, September 2000

Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET
journal, July 2016

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468
journal, June 2017

Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis
journal, December 2019

d-myo-Inositol 1-phosphate as a surrogate of d-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation
journal, November 2006

Structure-based discovery of opioid analgesics with reduced side effects
journal, August 2016

F13. Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of the Selective Orexin-1 Receptor Antagonist JNJ-61393215: Results From the First-In-Human and Multiple Ascending Dose Studies
journal, May 2019

The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene
journal, August 1999

Label-Free Kinetics: Exploiting Functional Hemi-Equilibrium to Derive Rate Constants for Muscarinic Receptor Antagonists
journal, August 2015

Determining the Potency and Molecular Mechanism of Action of Insurmountable Antagonists
journal, July 2006

Discovery and Characterization of ACT-335827, an Orally Available, Brain Penetrant Orexin Receptor Type 1 Selective Antagonist
journal, April 2013

Probing the activation-promoted structural rearrangements in preassembled receptor–G protein complexes
journal, August 2006

Differential expression of orexin receptors 1 and 2 in the rat brain
journal, January 2001

The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor
journal, September 2015

FRED and HYBRID docking performance on standardized datasets
journal, June 2012

The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness
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Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior
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Therapeutics development for addiction: Orexin-1 receptor antagonists
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Lemborexant: First Approval
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Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach
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Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs
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Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors
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Role of orexin receptors in obesity: from cellular to behavioral evidence
journal, March 2012

Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
journal, November 2018

Distribution of orexin receptor mRNA in the rat brain
journal, October 1998

Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia
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Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands: Binding kinetics contrast functional antagonism
journal, December 2013

Trends in GPCR drug discovery: new agents, targets and indications
journal, October 2017

Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs
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Orexin/hypocretin receptor signalling cascades: Orexin receptor signalling cascades
journal, December 2013

In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist
journal, May 2017

D ₄ dopamine receptor high-resolution structures enable the discovery of selective agonists
journal, October 2017

Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database
journal, March 2010

Repeated orexin 1 receptor antagonism effects on cocaine seeking in rats
journal, December 2012

Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant
journal, December 2014

Crystallizing membrane proteins using lipidic mesophases
journal, April 2009

Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists
journal, January 2015

The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases
journal, June 2018

A role for lateral hypothalamic orexin neurons in reward seeking
journal, August 2005

Multiplexing of Multicolor Bioluminescence Resonance Energy Transfer
journal, December 2010

Binding-Site Compatible Fragment Growing Applied to the Design of β ₂ -Adrenergic Receptor Ligands
journal, January 2018

FRED Pose Prediction and Virtual Screening Accuracy
journal, February 2011