TY - JOUR
T1 - Allosteric Modulation of Class A GPCRs
T2 - Targets, Agents, and Emerging Concepts
AU - Wold, Eric A.
AU - Chen, Jianping
AU - Cunningham, Kathryn A.
AU - Zhou, Jia
N1 - Funding Information:
This work was supported by Grants R21 MH093844 (J.Z. K.A.C.), R01 DA038446 (J.Z., K.A.C.), K05 DA020087 (K.A.C.), P30 DA28821 (K.A.C.), T32 DA07287 (E.A.W.), and F31 DA045511 (E.A.W.) from the National Institutes of Health, R. A. Welch Foundation Chemistry and Biology Collaborative Grant from the Gulf Coast Consortia (GCC), John Sealy Memorial Endowment Fund, and the Center for Addiction Research (CAR) at UTMB.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - G-protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented, and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials. Numerous class A GPCR allosteric modulators have been discovered recently, and emerging trends such as the availability of GPCR crystal structures, diverse functional assays, and structure-based computational approaches are improving optimization and development. This Perspective provides an update on allosterically targeted class A GPCRs and their disease indications and the medicinal chemistry approaches toward novel allosteric modulators and highlights emerging trends and opportunities in the field.
AB - G-protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented, and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials. Numerous class A GPCR allosteric modulators have been discovered recently, and emerging trends such as the availability of GPCR crystal structures, diverse functional assays, and structure-based computational approaches are improving optimization and development. This Perspective provides an update on allosterically targeted class A GPCRs and their disease indications and the medicinal chemistry approaches toward novel allosteric modulators and highlights emerging trends and opportunities in the field.
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U2 - 10.1021/acs.jmedchem.8b00875
DO - 10.1021/acs.jmedchem.8b00875
M3 - Article
C2 - 30106578
AN - SCOPUS:85052292560
VL - 62
SP - 88
EP - 127
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -