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Patricia H. Reggio

Patricia Reggio
Title Marie Foscue Rourk Professor and Head
Expertise Computational Biochemistry and Biomolecular Dynamics
Education B.S., Chemistry, Louisiana State University at New Orleans,1971
Ph.D., Physical Chemistry, University of New Orleans,1978
Postdoctoral Fellow, University of New Orleans,1979
Office Sullivan Science Building, Rm 435
Phone 336.334.5333
E-Mail Email Dr. Reggio

RESEARCH PROJECTS

The G-protein coupled receptor (GPCR) superfamily is one of the largest and most diverse protein families in nature.  GPCRs play important roles in a variety of biological and pathological processes such as neuromodulation, metabolic disorders, inflammation and pain. Not surprisingly, GPCRs are one of the most targeted protein families in pharmaceutical research today. My research group is a computational chemistry group that focuses on understanding the molecular basis for the effects of drugs on GPCRs. We are involved in large scale simulations of GPCRs embedded in lipid bilayers, as well as, in studies of the interactions of drugs with these proteins. Our calculations are carried out on a large, new GPU-enabled Linux cluster that is part of the Biomolecular Simulation and Bioinformatics Core Lab at UNCG. These calculations focus primarily on the cannabinoids (CBs), but also include the opioid, GPR35 and GPR55 systems.  We have established collaborations with medicinal chemists and pharmacologists such that compounds we design can be synthesized and evaluated.  We also have established collaborations with molecular biologists so that mutations that we design to test hypotheses concerning the importance of individual amino acid residues can also be generated and evaluated.  We use the resultant experimental information to improve our models, with the goal that at any given time, these models represent the current state of knowledge in the field.  Students in my lab can do purely computational projects or can do computational projects combined with rotations in labs of our experimental collaborators as part of their graduate projects.  A few examples of projects in progress in the lab are given below:

The Structure and Function of the Cannabinoid Receptor CB2 Homodimer and Its Signalling Complex (DA03934 and DA021358)

It has now become apparent that although GPCRs can signal as monomers, the actual signalling unit in the lipid bilayer is at least a dimer.  Using experimental  CB2 Substituted Cysteine Accessibility Method and Crosslinking Studies from the lab of Dr. Zhao-Hui Song at University of Louisville, we are building a model of the CB2 homodimer complex with Gi protein.  This system will be immersed in an atomistic representation of a fully hydrated lipid bilayer and the complex will be studied via microsecond timescale Molecular Dynamics calculations at IBM’s Thomas J Watson Research Facility in collaboration with Dr. Mike Pitman at IBM, Dr. Alan Grossfield at University of Rochester and Dr. Klaus Gawrisch at NIAAA.

 

Allosteric Modulators of the Cannabinoid Receptors. Supported by National Institutes of Health Grants (DA03934 and DA021358)

It is now recognised that many GPCRs contain allosteric binding sites for endogenous and/or synthetic ligands, which are topographically distinct from the agonist-binding site, which is known as the orthosteric site. In contrast to the direct effects on receptor function that are mediated by orthosteric ligands, allosteric drugs act by modulating receptor activity through conformational changes in the receptor that are transmitted from the allosteric to the orthosteric site and/or to effector coupling sites. One current project in my lab is looking at the allosteric modulator, ORG27569 and its effects on the affinity and signalling of the cannabinoid agonist, CP55,940. We are currently testing the computationally predicted allosteric binding site for ORG27569 via new compound synthesis with Dr. Herb Seltzman at Research Triangle Institute, mutation studies with Dr. Mary Abood at Temple University and pharmacological studies with Drs. Ruth Ross and Roger Pertwee at University of Aberdeen in Scotland. 

Mu Opioid Receptor Project. Supported by National Institutes of Health Grant  (DA023905)

We have developed computer models of the mu opioid receptor (MOR) in its inactive and active states and have begun simulating  MOR dimers.  In collaboration with Dr. Ping-Yee Law at University of Minnesota, we have recently examined the effects that cholesterol and receptor palmitoylation may play in signalling of the mu opioid receptor.  The effects appear to be on the  promotion of mu opiod receptor homodimerization at a TMH4/TMH4 interface.  We are currently exploring the effects of certain mutations in the MOR that turn classical MOR antagonists into agonists.

Identifying Ligands via High-Throughput Screening for the Newly Discovered Cannabinoid Receptor, GPR55. Supported by National Institutes of Health Grant (DA023204)

Results from GPR55-/- “knockout” mice indicate that GPR55 is involved in neuropathic pain.  Antagonists of GPR55, then, hold promise as new analgesics for this type of  pain. We have created models of GPR55 in its inactive and active states and are using these models to explore the interactions of the endogenous ligands, LPI and 2-AGPI at GPR55, as well as to explore the binding sites for several “hits” that have emerged from high-throughput screening of GPR55 in collaboration with Dr. Mary Abood at Temple University, Dr. Larry Barak at Duke University and Dr. Thomas Chung at the Sanford-Burnham Institute. Using these initial leads, more potent GPR55 antagonists are being designed at UNCG and synthesized by Dr. Mitch Croatt at UNCG.

RECENT PUBLICATIONS

  1. E. Kotsikorou, K. E. Madrigal, D. P. Hurst, H. Sharir, D. L. Lynch, S. Heynen-Genel, L. B. Milan, T. D.Y. Chung, H. H. Seltzman, Y. Bai, M. G. Caron, L. Barak, M. E. Abood and P. H. Reggio. “Identification of the GPR55 Agonist Binding Site Using a Novel Set of High Potemncy GPR55 Selective Ligands” Biochemistry. 50, 5633-5647 (2011).
  2. H. A. Iliff, D. L. Lynch, E. Kotsikorou, and P. H. Reggio. “Parameterization of Org27569: An Allosteric Modulator of the Cannabinoid CB1 G-Protein Coupled Receptor” J. Comput. Chem. (2011), in press
  3. E. Kotsikorou, D. L. Lynch, M.E. Abood, P.H. Reggio. “Lipid Bilayer Molecular Dynamics Study of Lipid- derived Agonists of the Putative Cannabinoid Receptor, GPR55” Chem. Phys. Lipids 164, 131-143 (2011).
  4. A.C. Howlett, P.H. Reggio, S.R. Childers, R.E. Hampson, N.M. Ulloa , D.G. Deutsch “Endocannabinoid Tone versus Constitutive Activity of Cannabinoid Receptors” Br. J. Pharmacol. 163, 1329-1343 (2011).
  5. D.F. Sitkoff, N. Lee, B.A. Ellsworth, Q. Huang, L. Kang, R. Baska, Y. Huang, C. Sun, A. Pendri, M. F. Malley, R. P. Scaringe, J. Z. Gougoutas, P. H. Reggio, W. R. Ewing, M. A. Pelleymounter, K. E. Carlson. "Cannabinoid CB(1) receptor ligand binding and function examined through mutagenesis studies of F200 and S383" Eur J Pharmacol. 651, 9-17 (2011).
  6. P. Zhao , H. Sharir, A. Kapur, A. Cowan, E.B. Geller, M.W. Adler, H.H. Seltzman, P.H. Reggio, S. Heynen- Genel, M. Sauer, T.D. Chung, Y. Bai, W. Chen, M.G. Caron, L.S. Barak, M.E. Abood. "Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity" Mol Pharmacol. 78, 560-568 (2010).
  7. D.P. Hurst, A. Grossfield, D.L. Lynch, Feller, S., Romo, T.D., K. Gawrisch, M.C. Pitman, P.H. Reggio. "A Lipid Pathway for Ligand Binding is Necessary for a Cannabinoid G Protein-Coupled Receptor" J. Biol. Chem. 285, 17954-17964 (2010).
  8. J. W. Huffman, S.A. Hepburn, P.H. Reggio, D.P. Hurst, J.L. Wiley, B.R. Martin, "Synthesis and Phamacology of 1-Methoxy Analogs of CP47497" Bioorg. Med. Chem. Epub June 22 (2010).
  9. P.H. Reggio “Endocannabinoid Binding to Cannabinoid Receptors:What is Known and What Remains Unknown" Curr. Med. Chem. 17, 1468-1486 (2010).
  10. P.H. Reggio “Toward the Design of Cannabinoid CB1 Receptor Inverse Agonists and Neutral Antagonists" Drug. Dev. Res. 70, 585-600 (2009).
  11. Y. Chen, C. Chen, E. Kotsikorou, D.L. Lynch, P.H. Reggio, L.Y. Liu-Chen.  “GEC1-{kappa} opiod receptor binding involves hydrophobic interactions: GEC1 has a chaperone-like effect" J. Biol. Chem. 284, 1673-1685 (2009).
  12. H. Fan, E. Kotsikorou, A. F. Hoffman, H. T. Ravert, D. P. Hurst, C. R. Lupica, P. H. Reggio, R. F. Dannals, A.G. Horti. “4-Cyanopyrazole derivatives of Rimonabant are cerebral cannabinoid receptor (CB1) ligands with potential as PET imaging agents” Eur. J. Med. Chem., 44, 593-609 (2009).
  13. N. M. Nebane, D. P. Hurst, C.A. Carrasquer, Z. Qiao, P. H. Reggio and Z.-H. Song. “Residues accessible in  the binding site crevice of transmembrane helix 6 of the CB2 cannabinoid receptor" Biochemistry  47, 13811-13821 (2008).
  14. Y. Pei, R. Mercier, J.K. Anday, G.A. Thakur, A.M. Zvonok, D.P.Hurst, P.H. Reggio, D.R. Janero, A. Makriyannis. "Ligand-binding architecture of human CB2 cannabinoid receptor:Evidence for receptor sub-type-specific binding motif and modeling GPCR activation" Chem Biol. 15, 1207-1219 (2008).
  15. R. M. Whitnell, D. P. Hurst, P. H. Reggio, F. Guarnieri. “Conformational Memories with Variable Bond Angles” J. Comput.Chem. 29, 741-752 (2008).
  16. Z. Sidló, P. H Reggio, M. E. Rice. “Inhibition of striatal dopamine release by CB1 receptor activation requires nonsynaptic communication via GABA, H2O2, and KATP channels” Neurochem. Int., 52, 80-88 (2008).

NIH PubMed Publications list for Patricia Reggio