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Feature Articles : May 1, 2008 ( )
GPCRs Remain “Hot” Drug Targets
A Flurry of Activity in the Field Has Resulted in New Methodologies that Increase Leads
GPCRs represent the largest family of genes expressed in the human genome, according to Jeremy Richman, Ph.D., associate director, cardiovascular biology, at Arena Pharmaceuticals. “Their cell membrane localization, the diversity of tissue expression, and the fact that they have the potential to elicit essentially every signaling pathway, makes these proteins ideal therapeutic targets.”
Informa Life Sciences’ “6th Annual Congress: G Protein-Coupled Receptors in Drug Discovery” conference in Berlin in mid-March showcased some spectacular discoveries in this scientific arena that, although years in the making, have only recently come to fruition.
“It is a really good time to be in this field,” said P. Jeffrey Conn, Ph.D., professor and director, Vanderbilt University program in drug discovery, and a keynote speaker at the conference. This well-established conference assembles leading experts from both academia and industry in the field of GPCR research, and as evidenced by the presentations, there was plenty of good news to share.
Dr. Conn’s presentation focused on his lab’s research. First, he spoke about selective activators of specific subtypes of metabotropic glutamate receptors (mGluRs) that have potential as therapeutic agents for psychiatric and neurological disorders. Specifically, he outlined studies suggesting the utility of mGluR5 activators as a treatment for schizophrenia. Unfortunately, the search for selective agonists for this receptor was unsuccessful. Successful antagonists were discovered though, and currently, three companies are pursuing clinical trials with these drugs.
Differentially Activated Signal-Transduction Pathways
Arena Pharmaceuticals is geared specifically to studying GPCRs, and Dr. Richman’s team is primed to look at therapeutic targets in cardiovascular health. One such therapeutic target is the high-affinity, nicotinic acid receptor GPR109A. This Gi-coupled receptor, expressed on adipocytes, macrophages, and Langerhans cells, is presumed to mediate the therapeutic actions of nicotinic acid. A water-soluble vitamin, nicotinic acid, at high doses favorably affects all lipid and lipoprotein parameters believed to be cardiovascular risk factors.
In Silico Screening
Approaches to in silico drug design for soluble proteins are becoming straightforward, albeit nontrivial, said Sid Topiol, Ph.D., associate director of computational chemistry at Lundbeck Research USA.
EPIX Pharmaceuticals is also advancing in silico modeling. “Our approach is unique in that we use PREDICT™, nonhomology algorithms, to model 3-D structures of GPCRs. We base lead identification and optimization on what the binding site looks like,” said Sharon Shacham, Ph.D., svp of drug development.
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