The candidate's overall research goal is to obtain rigorous mechanistic insight into the structure and dynamics of G Protein-Coupled Receptors (GPCRs) involved in drug abuse, thus contributing a level of molecular detail that is often difficult to obtain experimentally, yet it has direct implications on the rational discovery of improved therapeutics. Following her interest in integrating cutting-edge computational methods with state-of-the-art, powerful experimental approaches to generate testable hypotheses of receptor-receptor interactions leading to an understanding of the role of oligomerization in receptor function, the candidate is seeking an additional period of protected time to receive training in fluorescence-based experimental techniques and behavioral studies from a number of expert, long-term collaborators. Supported by strong institutional commitment, the candidate's specific long-term research objectives are: 1) To further contribute to the dynamic mechanisms of opioid receptors, 2) To develop tools aimed at advancing current understanding of the spatio-temporal organization of GPCRs in living cells, and its relation to function, and 3) To take full advantage of the recent high-resolution structural information available for GPCRs involved in drug abuse and use enhanced molecular dynamics (MD) simulations combined with virtual screening methods, functional studies, and structure-guided chemical synthesis, to discover novel, non-classical opioid ligands that, by targeting specific receptor conformations or oligomeric states, can either be developed into more effective therapeutics or serve as chemical probes to study receptor dynamics and function. Protected time under the auspices of a K02 renewal application is necessary because a) the candidate has no formal training in experimental biophysical techniques or behavioral studies, and b) some of the state-of-the-art biophysical techniques the candidate is interested in integrating with her computational studies are currently at the early stage of their development, and may require some extra time to establish themselves as means to achieve breakthrough mechanistic insight into the spatio-temporal organization of GPCRs in the cell membrane, and ultimately, its relation to function. The opportunity to participate in this early development has the advantage to take current understanding of the experiments to a much deeper level through focused training from experts in the field who happen to be long-term collaborators of the candidate. In summary, while pursuing her research plan, and incidentally providing mentorship for a number of postdoctoral and undergraduate students, the candidate will develop new skills and learn new methods that will advance her work and its potential to improve understanding of the structural bases of the functions of GPCRs, thus laying the foundation for establishing the potential value of targeting GPCR oligomers for the treatment of various nervous system disorders, including addiction and other mental illnesses. This is a very challenging undertaking, justified by the prospects of impacting significantly biomedical research through the discovery of improved drugs with lesser side effects.
This K02 renewal application is to support the continued career development and training of a female computational biophysicist whose research program focuses on advancing current understanding of the role of oligomerization in G protein-coupled receptor function.
|Marino, Kristen A; Shang, Yi; Filizola, Marta (2018) Insights into the function of opioid receptors from molecular dynamics simulations of available crystal structures. Br J Pharmacol 175:2834-2845|
|Marino, Kristen A; Filizola, Marta (2018) Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations. Methods Mol Biol 1705:351-364|
|Meral, Derya; Provasi, Davide; Prada-Gracia, Diego et al. (2018) Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations. Sci Rep 8:7705|
|Filizola, Marta (2018) Insights from molecular dynamics simulations to exploit new trends for the development of improved opioid drugs. Neurosci Lett :|
|Yano, Hideaki; Provasi, Davide; Cai, Ning Sheng et al. (2017) Development of novel biosensors to study receptor-mediated activation of the G-protein ? subunits Gs and Golf. J Biol Chem 292:19989-19998|
|Kapoor, Abhijeet; Martinez-Rosell, Gerard; Provasi, Davide et al. (2017) Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity. Sci Rep 7:11255|
|Schneider, Sebastian; Provasi, Davide; Filizola, Marta (2016) How Oliceridine (TRV-130) Binds and Stabilizes a ?-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways. Biochemistry 55:6456-6466|
|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 ? 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|
|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|
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