The impact of GPCR structures on pharmacology and structure‐based drug design

Abstract

After many years of effort, recent technical breakthroughs have enabled the X-ray crystal structures of three G-protein-coupled receptors (GPCRs) (b1 and b2 adrenergic and adenosine A2a) to be solved in addition to rhodopsin. GPCRs, like other membrane proteins, have lagged behind soluble drug targets such as kinases and proteases in the number of structures available and the level of understanding of these targets and their interaction with drugs. The availability of increasing numbers of structures of GPCRs is set to greatly increase our understanding of some of the key issues in GPCR biology. In particular, what constitutes the different receptor conformations that are involved in signalling and the molecular changes which occur upon receptor activation. How future GPCR structures might alter our views on areas such as agonist-directed signalling and allosteric regulation as well as dimerization is discussed. Knowledge of crystal structures in complex with small molecules will enable techniques in drug discovery and design, which have previously only been applied to soluble targets, to now be used for GPCR targets. These methods include structure-based drug design, virtual screening and fragment screening. This review considers how these methods have been used to address problems in drug discovery for kinase and protease targets and therefore how such methods are likely to impact GPCR drug discovery in the future. Pharmacology (2010) 159, 986-996; doi:10.1111/j.1476-5381.2009 published online 13 November 2009 This article is part of a themed section on Molecular Pharmacology of GPCR. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j. 1476-5381.2010.00695.x Keywords: G-protein-coupled receptor; X-ray crystallography; structure-based drug design; selectivity; conformation; dimerization; allosteric regulators; fragment screening; virtual screening; rhodopsin Abbreviations: BACE, b-site of APP cleaving enzyme; DPPIV, dipeptidyl peptidase-4; EGFR, epidermal growth factor receptor; FXa, Factor X; GPCR, G-protein-coupled receptor; HDAC, histone deacetylases; HTS, high-throughput screening; NAM, negative allosteric modulator; PAM, positive allosteric modulator; ROCK1, rho-associated; coiledcoil, containing protein kinase 1; SBDD, structure-based drug design; SPR, surface plasmon resonance; TM, transmembrane British Journal of IntroductionHigh-resolution 3-dimensional structures of proteins provide a detailed understanding of the form and function of such proteins at the molecular level. This is useful not only to describe the aspects of protein structure which underlie physiological processes but also in visualizing the intimate connections that bind proteins to their ligands and to small molecule drugs. Although structural studies have been highly successful for soluble proteins, progress in solving the structures of membrane proteins has been relatively poor. G-proteincoupled receptors (GPCRs) represent one of the most important classes of protein due to their critical role in ...

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

“…The results reported here are comparable to those from other similar works [19][20][21][22] which showed that GPCR modeling [23][24][25][26][27][28][29][30][31] in the absence of a crystal structure can be a valid replacement [32][33][34][35][36][37][38][39] for structural and functional exploration of GPCR receptors, and for the discovery [21,[40][41][42][43], VS [44][45][46][47][48][49][50][51][52] and optimisation [23,53] of their ligands.…”

Turning a protein kinase on or off from a single allosteric site via disulfide trapping

“…These compounds represent a diversity of scaffolds common in drugs and drug candidates (e.g., heterocycles, piperazines, etc.) and most obey the "Rule of 3," which was established to judge fragments as suitable starting points for drug discovery efforts (mass <300 Da, predicted cLogP ≤3, number of hydrogen-bond donors/acceptors ≤3) (14). Preliminary experiments revealed that the disulfide fragments reacted much more readily with the PDK1 Cys mutants than did the Cys-PIFtides; at 100 μM β-ME and 100 μM compound, most small molecule disulfides reacted quantitatively with every Cys mutant.…”

Fragment-based lead discovery: challenges and opportunities

“…On the other hand, companies whose target portfolios are increasingly filled with GPCRs and ion channels will find this approach less tractable. While there has been tremendous recent success in the isolation and X-ray structural analysis of membrane proteins [19,20], routine application of FBDD to these targets is still some time away [21].…”