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Meeting Summary
Sponsored by: National Institute on Drug Abuse
Symposium Chair: Dr. Rao S. Rapaka, NIDA
Co-Chairs: Dr. Paul Hillery, NIDA; Dr.Karen Skinner, NIDA
Meeting Summary
This symposium was organized to update the progress in this area and to explore the new areas of research to be encouraged in future and to promote research related to drug abuse and, more specifically to enhance NIDA's programs in drug design. The first talk of the symposium was given by Dr. James Colliver, NIDA and he presented an overview of the epidemiological patterns of some selected drugs of abuse. The second talk was from Dr. Jerome Karle, Nobel Laureate, Naval Research laboratories, and he was the keynote speaker. He gave an overview on quantum crystallography and all the recent developments in the area. Rest of the symposium consisted of four sessions, and the sessions were on, structure determination, receptors, transporters and mechanisms, structural genomics and proteomics and, ligands and therapeutics.
In the first session, Dr. Wlodawer reported on the determination of the crystal structure of a pepstatin-insensitive carboxyl proteinase from pseudomonas. Dr. Deschamps summarized some of the results from hundreds of ligands studied resulting from the NIDA-NRL interagency agreement. Dr. Choe described the structural parameters for calcium channels and Dr. Brennan spoke on multidrug binding proteins. Dr. Subramaniam gave a nice summary on the advances in the imaging of molecular assemblies with electron cryo-microscopy and this talk was later followed by Dr. Ramakrishnan on the molecular mechanical devices. Dr. Zuiderweg gave a presentation on the utilization of recent NMR techniques to study protein interactions and this talk was followed by Dr. Amzel's talk on the structure and mechanism of the mitochondrial ATP-synthase. Dr. Glaser gave a review on the techniques for crystallization of membrane proteins from connected-bilayer gels.
In the second session, Dr. Mark Mayer discussed the molecular mechanisms of desensitization for glutamate receptor ion channels. Dr. Kobilka's talk was on the ligand-specific conformational changes of the beta-2 adrenergic receptor, Dr. Javitch's talk was on oligomerization of the human dopamine receptor and the molecular mechanisms involved and Dr. Rudnick's presentation was on the serotonin transporter. Dr. Harel Weinstein gave a nice overview on signaling in membrane proteins and computational models of several transmembrane helices, role of proline in the formation of proline-kinks, and also presented data on the utilization of computational models to study molecular dynamics. Dr. Reggio described, from her computational studies, the structural features of the cannabinoid ligands for binding at the CB-1 receptor as inverse agonists. Dr. David Farrens gave a comparative study of the structural and structure-dependent functional properties of the cannabinoid and rhodopsin receptors. Dr. Mierke spoke on receptor-protien interactions using NMR and Dr. Patel gave an overview of FRET and demonstrated the applicability of this technique for the analysis of the ligand-receptor stoichiometry and aggregation states for three receptors systems. He demonstrated that this technique could be applied to live cells. Dr. Goodman demonstrated how the structural studies on the ligand-receptor system could help in ligand design.
In the third session, Dr. Patterson gave a summary of how proteomics techniques can be helpful in drug discovery, Dr. Cravatt gave an update on chemical approaches for functional proteomics and Dr. Gavin MaBeath gave an overview on protein microarrays and their applications to functional genomics and high-throughput screening. Dr. Stevens presented his talk on the application of high throughput techniques for drug design and Dr. Skolnick spoke on prediction of protein structure and function on a genomic scale. Dr. Neubig gave a talk on how RGS protein can serve as new targets for drug design for CNS therapeutics.
The last session was devoted to ligand design. Dr. Cascio spoke on the how the altered bilayer composition can effect the glycine receptor. Dr. Mosberg presented an impressive amount of data on ligand-receptor interactions and ligand design in the opioid area. Dr. Makriyannis described the design of cannabinoid ligands based in the structural biology models including the two new potent ligands, Mahanadamide and Paramandamide. Dr. Deber gave talk on polar mutations in membrane proteins and how these mutations may lead to genetic disease. Dr. Victor Hruby gave a overview of plasmon waveguide resonance spectroscopy and how this method can be used to differentiate agonist, antagonist and inverse agonist interaction without resorting to expense and laborious methods to synthesize labeled ligands.
These sessions were followed by several discussion sessions. Several recommendations have emerged from this symposium. There was an universal recognition among the participants that the time is ripe for undertaking a large number of structural biology studies and understanding the structure of ion channels, receptors, enzymes, proteins, lipids, and ligands is crucial. There was an agreement on developing new methodologies and application of presently available methods to the problems at hand. It was also suggested that bright chemists and biologists should be attracted to conduct research in this area by awarding "beginners grants" who could later really develop into established researchers concentrating in the CNS disorders and more specially in drug abuse research.