Allosteric small molecule modulators of nuclear receptors

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Abstract

Nuclear Receptors (NRs) are multi-domain proteins, whose natural regulation occurs via ligands for a classical, orthosteric, binding pocket and via intra- and inter-domain allosteric mechanisms. Allosteric modulation of NRs via synthetic small molecules has recently emerged as an interesting entry to address the need for small molecules targeting NRs in pathology, via novel modes of action and with beneficial profiles. In this review the general concept of allosteric modulation in drug discovery is first discussed, serving as a background and inspiration for NRs. Subsequently, the review focuses on examples of small molecules that allosterically modulate NRs, with a strong focus on structural information and the ligand binding domain. Recently discovered nanomolar potent allosteric site NR modulators are catapulting allosteric targeting of NRs to the center of attention. The obtained insights serve as a basis for recommendations for the next steps to take in allosteric small molecular targeting of NRs.
LanguageEnglish
Pages20-34
Number of pages15
JournalMolecular and Cellular Endocrinology
Volume485
DOIs
StatePublished - 1 Apr 2019

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Cytoplasmic and Nuclear Receptors
Allosteric Site
Ligands
Drug Discovery
Pathology

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title = "Allosteric small molecule modulators of nuclear receptors",
abstract = "Nuclear Receptors (NRs) are multi-domain proteins, whose natural regulation occurs via ligands for a classical, orthosteric, binding pocket and via intra- and inter-domain allosteric mechanisms. Allosteric modulation of NRs via synthetic small molecules has recently emerged as an interesting entry to address the need for small molecules targeting NRs in pathology, via novel modes of action and with beneficial profiles. In this review the general concept of allosteric modulation in drug discovery is first discussed, serving as a background and inspiration for NRs. Subsequently, the review focuses on examples of small molecules that allosterically modulate NRs, with a strong focus on structural information and the ligand binding domain. Recently discovered nanomolar potent allosteric site NR modulators are catapulting allosteric targeting of NRs to the center of attention. The obtained insights serve as a basis for recommendations for the next steps to take in allosteric small molecular targeting of NRs.",
author = "Meijer, {Femke A.} and {Leijten-van de Gevel}, {Iris A.} and {de Vries}, {Rens M.J.M.} and Luc Brunsveld",
year = "2019",
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day = "1",
doi = "10.1016/j.mce.2019.01.022",
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T1 - Allosteric small molecule modulators of nuclear receptors

AU - Meijer,Femke A.

AU - Leijten-van de Gevel,Iris A.

AU - de Vries,Rens M.J.M.

AU - Brunsveld,Luc

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Nuclear Receptors (NRs) are multi-domain proteins, whose natural regulation occurs via ligands for a classical, orthosteric, binding pocket and via intra- and inter-domain allosteric mechanisms. Allosteric modulation of NRs via synthetic small molecules has recently emerged as an interesting entry to address the need for small molecules targeting NRs in pathology, via novel modes of action and with beneficial profiles. In this review the general concept of allosteric modulation in drug discovery is first discussed, serving as a background and inspiration for NRs. Subsequently, the review focuses on examples of small molecules that allosterically modulate NRs, with a strong focus on structural information and the ligand binding domain. Recently discovered nanomolar potent allosteric site NR modulators are catapulting allosteric targeting of NRs to the center of attention. The obtained insights serve as a basis for recommendations for the next steps to take in allosteric small molecular targeting of NRs.

AB - Nuclear Receptors (NRs) are multi-domain proteins, whose natural regulation occurs via ligands for a classical, orthosteric, binding pocket and via intra- and inter-domain allosteric mechanisms. Allosteric modulation of NRs via synthetic small molecules has recently emerged as an interesting entry to address the need for small molecules targeting NRs in pathology, via novel modes of action and with beneficial profiles. In this review the general concept of allosteric modulation in drug discovery is first discussed, serving as a background and inspiration for NRs. Subsequently, the review focuses on examples of small molecules that allosterically modulate NRs, with a strong focus on structural information and the ligand binding domain. Recently discovered nanomolar potent allosteric site NR modulators are catapulting allosteric targeting of NRs to the center of attention. The obtained insights serve as a basis for recommendations for the next steps to take in allosteric small molecular targeting of NRs.

U2 - 10.1016/j.mce.2019.01.022

DO - 10.1016/j.mce.2019.01.022

M3 - Article

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JO - Molecular and Cellular Endocrinology

T2 - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

ER -