G-protein coupled receptors: Structure, function and design of novel chemical modulators
Title: G-protein coupled receptors: Structure, function and design of novel chemical modulators
DNr: SNIC 2014/1-262
Project Type: SNIC Medium Compute
Principal Investigator: Hugo Gutierrez de Teran <hugo.gutierrez@icm.uu.se>
Affiliation: Uppsala universitet
Duration: 2014-09-29 – 2015-10-01
Classification: 10601 10610 10407
Homepage: http://gpcr-modsim.org/
Keywords:

Abstract

G Protein-coupled Receptors (GPCRs) are the largest family of membrane receptors in the human genome. These transmembranal proteins are in charge of signal transduction across cellular membranes, and because of the many responses to hormones and neurotransmitters that they mediate, it is not surprising the importance of these receptors for the pharmaceutical industry: it is estimated that between 30 and 40% of the marketed drugs target a GPCR to any extent, including many blockbusters in the pharmaceutical industry. The relevance of these proteins in the control of the physiological equilibrium, together with the recent blossom in their structural characterization, partially explain that the recent Nobel prize in Chemistry (2012) awarded to the pioneering researchers in the molecular biology of GPCRs. This new scenario where structural information on GPCRs is becoming increasingly available to the scientific community has a positive impact in the design of novel compounds with computational methods, an area where our group has demonstrated a long tradition and remarkable success. One particularly intriguing aspect on GPCRs biology is the fact that these receptors might associate in order to function as supramolecular complexes: from dimers (homo and hetero) to higher order oligomers. Dimerization may alter receptor pharmacology, signaling, trafficking, subcellular localization, and desensitization. Oligomerization has been described to influence the pharmacology and biology of the family of adenosine receptors, in which our group has an established research line in collaboration with medicinal chemists and pharmacologists from the University of Santiago de Compostela. Within this long-term project, we have recently started to assess the design of novel compounds that modulate A3 receptor homodimers, and plan to extend this study to other dimers described for the adenosine receptors. Here, the purpose of the present application is to provide the necessary computational infrastructure to pursue the goals of this project as detailed below: • First, to explore different homodimer models of A1, A2A and A2B and A3 Adenosine receptors. We will use protein-protein docking and all-atom molecular dynamics simulations in the physiological environment of a hydrated lipid bilayer. This work might highlight the structural and dynamic role of the key residues involved in the interface contact of the homo/hetero - dimer, as well as the major protein motions, and provide with the refined molecular models to use as a basis to design novel ligands (see next point). • The second part of the project will aid future structure-based drug design efforts on these pharmacological targets. The study is based on the rational design of new antagonists and divalent drugs that may inhibit the protein dimerization, on the basis of preliminary results obtained in collaboration with the medicinal chemistry of our collaborator Prof. Eddy Sotelo (U. Santiago de Compostela). The outcome of this project will definitely contribute to the long-term chemical biology project established between our group and our experimental partners, which will ultimately allow the development of new strategies with therapeutically implications in diseases.