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Molecular modeling of G protein-coupled receptors

G 蛋白偶联受体的分子建模

基本信息

批准号：
7593399
负责人：
Stefano Costanzi
金额：
$ 44.45万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7593399
关键词：
3-Dimensional Adrenergic Receptor Agonist Antidiabetic Drugs Binding Binding Sites Bioinformatics Biological Bos taurus Calcium Calcium-Sensing Receptors Catecholamines Cattle Cell membrane Chemicals Class Collaborations Computer Assisted Computing Methodologies Consensus Databases Diabetes Mellitus Discipline Disease regression Docking Drug Kinetics Eligibility Determination Environment Epinephrine Evaluation Exhibits Family Study Fibrinolytic Agents Fluorine G-Protein-Coupled Receptors Generations Glycoproteins Goals Homology Modeling Hormone Receptor Hormones Human Individual Ions Knowledge Laboratories Lead Ligands Light Lipid Bilayers Marketing Membrane Proteins Metabolism Modeling Modification Molecular Molecular Models Molecular Structure Molecular Weight Mutagenesis N-terminal Names National Institute of Diabetes and Digestive and Kidney Diseases Nonesterified Fatty Acids Norepinephrine North Carolina Nucleotides Numbers Osteoporosis Parathyroid Hormones Pharmaceutical Preparations Pharmacologic Substance Phylogenetic Analysis Physiological Platelet aggregation Pliability Purpose Quantitative Structure-Activity Relationship Regulation Research Research Methodology Resources Rhodopsin Rodent Role Score Screening procedure Secondary Hyperparathyroidism Solutions Stimulus Structure Structure-Activity Relationship Study models Techniques Testing Thyrotropin Thyrotropin Receptor Thyrotropin-Releasing Hormone Thyrotropin-Releasing Hormone Receptors Time Transmembrane Domain Universities Venus Flytrap analog base blood glucose regulation cheminformatics computer studies design drug discovery extracellular human PTH protein improved in vivo interest molecular dynamics molecular modeling molecular recognition novel polypeptide receptor research study small molecule three dimensional structure tool virtual

项目摘要

Study of the structure-function relationships of the P2Y receptors. P2Y receptors are GPCRs activated by extracellular nucleotides. In collaboration with the laboratories of Drs. Kenneth Jacobson (NIDDK) and Kendall Harden (University of North Carolina), for the past few years I have been conducting bioinformatics and molecular modeling studies intended to shed light onto the structure-function relationships of the P2Y receptors. I have modeled all the known subtypes of the human P2Y receptors based on the structure of Rhodopsin and I have conducted molecular dynamics experiments in explicit a lipid bilayer environment. I have successfully predicted the conformational requirements of nucleotides for binding to the P2Y receptors and have rationally designed novel potent and selective agonists. I am particularly interested in antagonists of the P2Y1 subtype, which have been demonstrated to impede platelet aggregation in vivo and have a strong potential to be developed into antithrombotic agents. At this purpose, I have generated a model capable of predicting the activity of P2Y1 antagonists on the basis of their molecular structures (QSAR) and of their energy of interaction with the receptor model. In particular, I have devised LIST-CM (Ligand and Structure-based Consensus Modeling) which combines ligand-based and structure-based techniques into a single PLS regression model. Tested with a challenging set of novel P2Y1 antagonists, LIST-CM outperformed any individual model both in terms of internal and external predictivity. LIST-CM promises to be a viable scoring tool to be generally applied to lead-optimization projects. Currently, I am conducting a virtual screening of for non-nucleotide P2Y1 antagonists as potential antithrombotic agents with improved stability and pharmacokinetics. Structural characterization of the GPR40 and identification of novel ligands. GPR40 is a GPCR activated by long chain free fatty acids (FFAs), which is involved in the regulation of metabolic processes and glucose homeostasis. In particular, GPR40 is considered an appealing target for the treatment of type two diabetes. Our research, in collaboration with the laboratory of Dr. Marvin Gershengorn (NIDDK), is intended for the elucidation of the structure-function relationships of GPR40 and for the discovery of novel ligands. Our molecular modeling studies have been based on a homology modeling approach using rhodopsin as structural template. By means of molecular modeling supported by mutagenesis, we have identified the putative binding pocket for FFAs and synthetic ligands. In particular, we have pinpointed several residues important for agonist recognition and activation. Furthermore, by means of a virtual screening, we have identified novel and diverse GPR40 agonists and antagonists, which offer ground for the generation of potential antidiabetic agents. Structural characterization of the TRH-Rs and identification of novel ligands. Thyrotropin-releasing hormone (THR) is a tripeptide hormone which stimulates the release of thyrotropin by activating specific GPCRs known as thyrotropin-releasing hormone receptors (TRH-Rs). Two different TRH-R subtypes have been identified in rodents. The goal of our research, in collaboration with the laboratory of Dr. Marvin Gershengorn (NIDDK), is the elucidation of the structure-function relationships of the two subtypes and the identification of novel ligands able to discriminate against them. Such tools would be useful to shed light on the physiological roles of the two subtypes. By means of rhodopsin-based homology modeling, molecular dynamics in lipid bilayer, and Monte Carlo conformational searches, we compared the two subtypes identifying a correlation between the higher flexibility and higher basal activity of TRH-R2 versus the lesser flexibility and lower basal activity of TRH-R1. Molecular docking and mutagenesis also pinpointed subtle differences in the interaction of TRH with the two TRH-R subtypes. Furthermore, we performed a purely structure-based virtual screening and identified several novel antagonists of the TRH-Rs. Notably, the most potent compound, in its stereochemically pure form, is the first known small molecule ligand that exhibits a significant degree of selectivity toward one of the two TRH-R subtypes. In general, our structure-based virtual screening protocol offers an appealing solution to the problem of lead identification when the 3D structure of the receptor is known but there is no knowledge of the ligands. Identification of small molecules active as ligands of the Glycoprotein Hormone Receptors. Glycoprotein Hormone Receptors (GPHRs) are GPCRs activated by extracellular hormones that bind to their N-terminal regions. The goal of our research is the identification of small molecules that bind to the transmembrane domain of GPHRs, consequently activating or blocking the receptors. In particular our research, in collaboration with the laboratory of Dr. Marvin Gershengorn (NIDDK), focuses on the identification of agonists and antagonists of the thyroid-stimulating hormone receptor (TSHR). Our modeling studies have been directed toward the study of the interactions between the TSHR and low molecular weight ligands and to the design of modulators with improved potency and selectivity. Our efforts led to the identification of a binding pocket for small molecules within the transmembrane domain of TSHR. Furthermore, interactions fundamental for molecular recognition were identified and probed by mutagenesis and chemical modification of the ligands. Characterization of the binding site of allosteric modulators of the human calcium sensing receptor. Calcium sensing receptors (CaR) is a class III GPCR activated by extracellular Ca2 ions, which bind primarily to their extracellular Venus flytrap. Positive allosteric modulators cause a decrease in secretion of parathyroid hormone, and may be useful in the treatment of primary and secondary hyperparathyroidism. Negative allosteric modulators stimulate endogenous parathyroid hormone secretion and thereby having the potential to be used in the treatment of osteoporosis. Our research, in collaboration with the laboratory of Dr. Allen Spiegel (NIDDK), has focused on the identification of novel allosteric modulators, which bind to the 7TMs of the human CaR, and to the study of their interaction with the receptor. Study of the interactions of fluorinated epinephrine analogs with the adrenergic receptors. Adrenergic receptors are GPCRs activated by the extracellular catecholamines epinephrine and norepinephrine. Our research, in collaboration with laboratories of Drs. Kenneth Kirk and Jurgen Wess (NIDDK), is intended to shed light into the structure-function relationships of the receptors, in particular in relation to the dramatic effect that fluorine substituents have on the selectivity of the ligands for the various subtypes.

P2Y受体结构-功能关系的研究。