Chemical Diversity in the G Protein-Coupled Receptor Superfamily

Márton Vass; Albert J Kooistra; Dehua Yang; Raymond C Stevens; Ming-Wei Wang; Chris de Graaf

doi:10.1016/j.tips.2018.02.004

Chemical Diversity in the G Protein-Coupled Receptor Superfamily

Trends Pharmacol Sci. 2018 May;39(5):494-512. doi: 10.1016/j.tips.2018.02.004. Epub 2018 Mar 22.

Authors

Márton Vass¹, Albert J Kooistra¹, Dehua Yang², Raymond C Stevens³, Ming-Wei Wang⁴, Chris de Graaf⁵

Affiliations

¹ Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, Amsterdam 1081 HZ, The Netherlands; M.V. and A.J.K. contributed equally to this review.
² The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Pudong, Shanghai 201203, China.
³ iHuman Institute, ShanghaiTech University, 393 Hua Xia Zhong Road, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai 201210, China; Bridge Institute, Department of Chemistry and Biology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: stevens@shanghaitech.edu.cn.
⁴ The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Pudong, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai 201210, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: mwwang@simm.ac.cn.
⁵ Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, Amsterdam 1081 HZ, The Netherlands. Electronic address: c.de.graaf@vu.nl.

PMID: 29576399
DOI: 10.1016/j.tips.2018.02.004

Abstract

G protein-coupled receptors (GPCRs) are the largest family of cell signaling transmembrane proteins that can be modulated by a plethora of chemical compounds. Systematic cheminformatics analysis of structurally and pharmacologically characterized GPCR ligands shows that cocrystallized GPCR ligands cover a significant part of chemical ligand space, despite their limited number. Many GPCR ligands and substructures interact with multiple receptors, providing a basis for polypharmacological ligand design. Experimentally determined GPCR structures represent a variety of binding sites and receptor-ligand interactions that can be translated to chemically similar ligands for which structural data are lacking. This integration of structural, pharmacological, and chemical information on GPCR-ligand interactions enables the extension of the structural GPCR-ligand interactome and the structure-based design of novel modulators of GPCR function.

Keywords: G protein-coupled receptor (GPCR); structural cheminformatics.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Allosteric Regulation
Chemistry, Pharmaceutical
Drug Design
Humans
Ligands
Polypharmacology
Receptors, G-Protein-Coupled / chemistry*
Structure-Activity Relationship

Substances

Ligands
Receptors, G-Protein-Coupled