Chemical Biology Discussion Group

Organizer: Bruce Baron, Aventis

It is hoped that this group will provide a forum for lively discussion and for establishing connections, and perhaps collaborations, between chemists armed with novel technologies and biologists receptive to using these approaches to solve their chosen biological problem.

Program

6:00–6:45
Keynote Presentation:

Brian Kobilka, Stanford University, "Conformational Dynamics of the Beta 2 Adrenoceptor: The Effect of Ligand Structure on Receptor Structure."

6:45–7:45
Short Presentations:

Felix Sheinerman, Aventis Research, "Toward Genome-Wide Analysis of Ligand Binding Specificity: Protein Kinases and GPCRs."

Wayne Childers, Wyeth Research, "SRA-333: A 5-HT1A Receptor Antagonist for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease."

Abstracts

"Conformational Dynamics of the Beta 2 Adrenoceptor: The Effect of Ligand Structure on Receptor Structure"
Brian Kobilka
G protein–coupled receptors (GPCRs) constitute the largest family of receptors in the human genome and are important targets for drug discovery. The beta 2 adrenoceptor is a prototypical family A GPCR that mediates physiologic responses to adrenaline and noradrenaline. In cells, the function of the beta 2 adrenoceptor can be modulated by a spectrum of synthetic ligands, including full agonists (maximal activation), partial agonists (submaximal activation), neutral antagonists (no biological effect), and inverse agonists (inhibit basal activity). A discussion will ensue on the biochemical and biophysical approaches to map the conformational changes that occur following the binding of these different classes of ligands. Also discussed will be efforts to characterize dynamic properties of the beta 2 adrenoceptor structure (the existence of distinguishable conformational states and the transitions between states) in the presence of various drugs.

"Toward Genome-Wide Analysis of Ligand Binding Specificity: Protein Kinases and GPCRs"
Felix Sheinerman
The ability to predict which members of a protein family bind a particular ligand has a number of important applications in drug design, including rational improvement of ligand selectivity, identification of novel targets and antitargets for drug candidates, and design of a la carte chemical libraries tailored to individual protein family members. This talk will describe a computational strategy for the analysis of sequence and structural determinants of ligand-binding selectivity of members of large protein families. Analysis of the protein kinase family—a family comprising proteins with a large amount of experimental data available—reveals that all kinases that bind a given inhibitor with high affinity can be identified based on the analysis of sequence variability at the specific positions calculated to be important for binding. Challenges posed by G protein–coupled receptors and benchmarking of ab initio methods for GPCR 3D structure predictions will be discussed.

"SRA-333: A 5-HT1A Receptor Antagonist for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease"
Wayne Childers
The G protein–coupled serotonin 5-HT1A receptor has been an important drug discovery target for over a decade, due to its role in regulating multiple systems implicated in psychiatric diseases. Potential therapeutic indications for 5-HT1A antagonists include nicotine withdrawal, enhancement of SSRI-induced antidepressant activity, and the treatment of cognitive dysfunction. The discovery of WAY-100635 provided the field with the first selective 5-HT1A full antagonist. However, the lack of oral bioavailability for this compound prompted us to design and synthesize several classes of arylpiperazine-based molecules. The ensuing SAR studies reve