SBIR-STTR Award

A novel approach to drug discovery is being tested on an antiobesity G protein-coupled receptor target. Currently, a Combinatorial Chemistry (CC) library is screened against a receptor target by High Throughoutput Screening (HTS). We will randomize the receptor's binding site creating a Combinatorial Biology (CB) library. This CB library will contain multiple receptor variants with novel recognition properties. Screening the CC library against the CB library scales up the number of putative ligand-receptor interactions studied (and the number of leads identified) by the number of receptor variants (l00-l0(4) fold). This ligand-variant receptor data will be analyzed matching changes in chemical moieties with amino acid changes. This information should greatly facilitate developing a wild-type lead, and in general the lead optimization process. A Cre-mediated single-target site integration has been engineered in NIH3T3 cells, allowing expression of a single receptor per cell. The promiscuous G-alphal6 will be stably transfected to support coupling of the receptor to Ca++ signals. For this feasibility study, a 120 single receptor variants will be expressed in NIH3 T3-Cre-G16 cells. The ability to measure simultaneously different receptor variants responses to a selective agonist in our functional assay will support the feasibility of the Split-Maze approach. PROPOSED COMMERCIAL APPLICATIONS: Our goal is to 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 target receptor and can screen thousands of receptor variants in one step. The new approach has the potential to develop higher quality leads, faster and cheaper than current state of the art

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