Modeling the Structure-Activity of Chemokine Receptors
DESCRIPTION (provided by applicant): Understanding the precise molecular interactions between drugs and their targets, their structure-activity relationship (SAR), is a highly desirable goal during drug development. Elucidation of SAR for G protein-coupled receptors (GPCRs) is a complicated task because direct structural visualization of these proteins is difficult or impossible. We have created a product, the Structure-Activity Relationship Array (SARray), that enables structural and functional interactions of drug candidates with GPCRs to be determined at the detailed level of amino acid side-chain interactions. The primary goal of this proposal is to create a tool that will facilitate drug optimization for GPCRs. The prototype SARray, developed and tested in Phase 1, will focus on the chemokine receptor CCR5. SARrays for all twenty chemokine receptors will be developed in Phase 2, and customized SARrays for any membrane protein will be offered in Phase 3. These arrays (our physical product) will be sent to customers with protocols and support for array analysis and processing. In preliminary experiments, we created a prototype CCR5 SARray. The SARray was rapidly assayed for five different functions, including evaluation of antibody binding epitopes and HIV-1 coreceptor function. Relevant molecular interactions were identified, even within our small-scale library, suggesting that our strategy for SAR analysis of GPCRs can be accomplished. The Specific Aims of our Phase I proposal are: Specific Aim I. Create a Comprehensive SARray in which the Functional Role of Every Amino Acid of a GPCR can be Assayed. Specific Aim II. Analyze Structure-Activity Relationships of a GPCR.
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