This KO2 application seeks support from NIDA for Dr. Marta Filizola's continued career development as an independent investigator. Her overall career goal is to contribute to the advancement in knowledge towards a better understanding of the molecular mechanisms underlying G-protein coupled receptor (GPCR)-mediated actions of drugs of abuse by means of computational methodologies that range from bioinformatics to modeling and simulation. In view of the recently established role and importance of GPCR oligomerization in receptor function, current research objectives of the Filizola laboratory are: a) To build refined three-dimensional (3D) models of GPCR oligomers;b) To build activated states of GPCR complexes in the interaction with their G-proteins;c) To study the dynamics of active and inactive GPCR complexes, so as to identify the molecular determinants responsible for allosteric modulation of GPCR function;d) To identify the molecular determinants responsible for the specificity of GPCR oligomerization and functional plasticity;and e) To develop, interpret and disseminate to the scientific community detailed information about the structural context of GPCR oligomerization and its experimentally determined implication for mechanisms of drug abuse. These research objectives are embodied in the proposed aims of the applicant's two currently funded NIDA projects, RO1 DA020032 and R21/R33 DA017976. In pursuit of these long-term research goals, the objectives of the current KO2 application include: 1) freeing the applicant from some teaching and administrative duties to devote nearly full time to develop further her research studies on GPCRs involved in mechanisms of drug abuse;2) advancingthe applicant's progress in becoming a leader in computational studies of GPCR dimers/oligomers;and 3) intensifying the applicant's training in experimental techniques currently used to study structure, function, and dynamics of GPCR dimers/oligomers. Career development activities proposed in this application include interactions and collaborations designed to expose the applicant to novel computational methodologies as well as molecular and biophysical experimental techniques in vitro and in vivo.
Understanding of GPCR function has recently been challenged by experimental evidence that several of these receptors are organized in the cell membrane as oligomers with unique pharmacological properties. Oligomeric models of GPCRs resulting from use of computational approaches further supported by experiments are expected to help design more effective and selective agents for therapeutic purposes.
|Shang, Yi; Yeatman, Holly R; Provasi, Davide et al. (2016) Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors. ACS Chem Biol 11:1220-9|
|Wardman, Jonathan H; Gomes, Ivone; Bobeck, Erin N et al. (2016) Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Sci Signal 9:ra55|
|Crowley, Rachel Saylor; Riley, Andrew P; Sherwood, Alexander M et al. (2016) Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting Î¼ Opioid Analgesic with Reduced Abuse Liability. J Med Chem 59:11027-11038|
|Kruegel, Andrew C; Gassaway, Madalee M; Kapoor, Abhijeet et al. (2016) Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J Am Chem Soc 138:6754-64|
|Schneider, Sebastian; Provasi, Davide; Filizola, Marta (2016) How Oliceridine (TRV-130) Binds and Stabilizes a Î¼-Opioid Receptor Conformational State that Selectively Triggers G Protein-Signaling Pathways. Biochemistry :|
|Provasi, Davide; Boz, Mustafa Burak; Johnston, Jennifer M et al. (2015) Preferred supramolecular organization and dimer interfaces of opioid receptors from simulated self-association. PLoS Comput Biol 11:e1004148|
|Bisignano, Paola; Burford, Neil T; Shang, Yi et al. (2015) Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the Î¼-Opioid Receptor. J Chem Inf Model 55:1836-43|
|Burford, Neil T; Livingston, Kathryn E; Canals, Meritxell et al. (2015) Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the Î´-opioid receptor. J Med Chem 58:4220-9|
|Schneider, Sebastian; Provasi, Davide; Filizola, Marta (2015) The Dynamic Process of Drug-GPCR Binding at Either Orthosteric or Allosteric Sites Evaluated by Metadynamics. Methods Mol Biol 1335:277-94|
|Shang, Yi; Filizola, Marta (2015) Opioid receptors: Structural and mechanistic insights into pharmacology and signaling. Eur J Pharmacol 763:206-13|
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