Version 2.1.1.0

Abstract

Grant Number:	5R44DK057966-03
PI Name:	BALLESTEROS, JUAN
PI Email:	jballesteros@novasite.com
PI Title:
Project Title:	Split-Maze Discovery of Antiobesity Drugs

Abstract: DESCRIPTION (Scanned from the Applicant's Abstract): At Novasite, we have developed a novel system capable of screening compound libraries against thousands of variants of the melanocortin-4 receptor simultaneously, at little additional cost relative to wild type only screening systems. This new technology allows a novel approach to drug discovery, called the Split-Maze, based on the large scale generation and screening of variant receptors. We randomize the receptor's binding site residues, resulting in expanded receptors with enhanced recognition properties. For lead identification, we screen each compound against thousands of variant receptors which results in identifying novel and high potency lead compounds which act on variant receptors. For Lead Optimization, we first identify the key interactions between the chemical moieties of the lead compound and individual residues within the receptor so as to guide docking of the compound into the receptor's binding site, resulting in a biochemically derived structural model of the lead-receptor complex. In addition, we analyze the changes in the identified lead-receptor interactions to enhance the potency of the lead compound towards the receptor. The structural template will then be used to convert the amino acid changes that enhance the lead's potency into mirror-image modifications proposed on the chemical compound, so as to optimize the lead compound's potency. PROPOSED COMMERCIAL APPLICATION: Our goal is discover a novel agonist to the melanocortin-4 receptor, which would be a potential antiobesity drug. Conservative estimates predict a >5 billion market of an antiobesity drug by the year 2005. We are developing a novel approach to drug discovery that incorporates combinatorial biology on the receptor and can screen thousands of receptor variants in one step. This new approach has the potential to develop higher quality leads, faster and cheaper than the current state of art.

Thesaurus Terms:
G protein, binding site, combinatorial chemistry, drug discovery /isolation, obesity, receptor binding, weight control agent
chemical registry /resource, genetic library, hormone receptor
cell line, high throughput technology, transfection

Institution:	NOVASITE PHARMACEUTICALS, INC.
	11095 FLINTKOTE AVE
	SAN DIEGO, CA 92121
Fiscal Year:	2003
Department:
Project Start:	01-SEP-2000
Project End:	30-NOV-2003
ICD:	NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
IRG:	ZRG1

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