Title:	G-protein coupled receptors: Structure, function and design of novel chemical modulators
DNr:	SNIC 2015/1-304
Project Type:	SNIC Medium Compute
Principal Investigator:	Hugo Gutierrez de Teran <hugo.gutierrez@icm.uu.se>
Affiliation:	Uppsala universitet
Duration:	2015-10-01 – 2016-10-01
Classification:	10601 10610 10407
Homepage:	http://gpcr-modsim.org/
Keywords:

Abstract

G-Protein coupled Receptors (GPCRs) are transmembranal proteins in charge of signal transduction across cellular membranes. The mature stage of the research in this field have been recognized with the Nobel prize in Chemistry (2012), and the biomedical relevance is clear with 40% of the marketed drugs target a GPCR. We have longstanding experience on the structural biology and ligand design of GPCRs. We have several projects, alone or in collaboration with experimental groups, aimed to understand the GPCR structure-function relationship and to assist in the GPCR ligand design process. Hence, we will continue our project(SNIC 2014/1-262) as follows: • Development of an MD protocol for the refinement of GPCR structural models. As part of our webserver for the 3D structural modeling of class-A GPCRs, (see http://gpcr-modsim.org), we have developed a standalone python wrapper for the GROMACS MD package, which performs a careful process of membrane insertion and equilibration protocol for the modeled GPCR. The latest version detects a conserved set of pair interactions between the alpha-helical regions, (Venkatakrishnan, Nature, 2013 Nature 494:185), which are then implemented as a series of NMR-style distance restraint functions in our equilibration protocol. We will here perform an extensive testing to assess the benefit of the NMR-style restraints on GPCR homology-based models. • Structure-based design of selective agonist ligands for the angiotensin II receptor type 2 (AT2). This program is running in collaboration with with Prof. Anders Hallberg (Medicinal Chemistry, Uppsala University). In a first stage, we used homology modeling and protein-ligand docking to understand how non-peptide antagonists designed by prof Hallberg interact with the angiotensin II receptors (AT1 and AT2, sharing 34% sequence homology). In the present proposal, we will use molecular dynamics simulations coupled to the linear interaction energy (LIE) method to assist on the design of chemical modifications of these ligand series. Furthermore, the role of key residues involved in ligand binding will be analyzed with our free energy perturbation (FEP) protocols (Keränen, Chem. Commun., 2015, 51, 3522) which will allow understanding of AT1/AT2 selectivity. • Design of peptidic agonists of the neuropeptide Y (NPY) type-2 (Y2) receptor. The Y2 receptor is a GPCR that regulates appetite, which makes it a potential target for treatment of obesity. In collaboration with the Neurosciences department (Professor Dan Larhammar), we will here analyze the effect of several point mutations in the receptor and chemical modifications on selected positions of the natural agonist (the PYY peptide) with our FEP protocols. The results obtained will be used to design more potent and selective agonists. • Ligand design for the family of adenosine receptors. Our collaboration with Prof. Eddy Sotelo (University of Santiago de Compostela) is aimed to discover novel chemical scaffolds targeting each of the four Adenosine receptors. Here, we will use a combination of LIE and FEP methodologies to establish clear structure-activity relationships of existing ligand series and assist in the rational design of more potent and selective ligands.