The role of experimental and computational structural approaches in 7TM drug discovery

Abstract

Introduction: Starting with the published X-ray structures of ligand-mediated 7TM proteins in 2007, experimental approaches, led by X-ray structure determinations, and computational approaches, led by docking and molecular dynamics, have converged to elaborate our understanding of this field and demonstrate their effectiveness in drug discovery.

Areas covered: The authors review the structural information that has emerged for ligand-mediated 7TM proteins, including the class A, B, C, and F receptors, focusing on the 7TM domains for the multi-domain proteins. The authors describe the key regions associated with ligand binding as well as features responsible for function such as activation versus inhibition and biased signaling. Furthermore, the authors summarize the effectiveness of computational studies to help clarify the structure–function information and their use for drug discovery.

Expert opinion: There is now a significant amount of structural information covering a range of 7TM protein classes (A, B, C, and F) and activation states. For these and closely related proteins, structure-based drug discovery has proven to be a powerful tool. More structural information is needed with respect to dimerization, 7TM proteins with β-arrestin to help in understanding the control of biased signaling, and full-protein structure determinations for non-class A proteins to help in understanding and controlling their functioning. Finally, the use of the existing structural information to target new sites on these proteins needs further exploration.

Keywords:

• computer-aided drug discovery
• docking
• drug design
• G-protein coupled receptors
• GPCRs
• X-ray structure

Declaration of interest

S Topiol is Chief Scientific Officer and M Sabio is a Principal Investigator for 3D-2Drug. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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