The process of drug design currently begins with a drug lead and/or target. It involves the refinement of that lead and target combination to achieve optimal specificity for high efficacy and reduced off-target effects. The proposed exploratory technology development program focuses on the discovery of a new platform for drug design that identifies both lead and target in parallel. It combines the recently emerged ?protein-templated fragment ligation (PTFL)? concept with underexplored Paal-Knorr chemistry. For the purpose of technology development, we have centered our efforts on the identification of new leads and targets for pain. This model provides an ideal arena for technology development since opioid misuse in the United States has attained epidemic proportions while targeting established proteins such as COX-2 has reached a threshold generating an emergent need to rapidly discover and explore alternative targets. As the first Specific Aim, we will demonstrate the use of the proposed platform by employing the Paal-Knorr reaction to deliver novel COX-2 pyrrole-containing probes, hits and leads. As many targets cannot be expressed and used in vitro, we will then focus on translating the platform to operate in mammalian cells. As the second Specific Aim, we will demonstrate how our method can be used to identify probes to unexplored targets. While developed for the discovery of new leads for pain, the proposed approach is general in nature and can be applied for therapeutic discovery for a wide range of ailments including but not limited to cancer, neurodegenerative diseases, stroke, and infectious disease. If successful, this technology and expansions thereon could add an important next-generation tool to further revolutionize the drug discovery process.
. There is an immediate need for new platforms for therapeutic discovery. This program explores the first step in the discovery process that unveils both drug targets and leads in parallel and it involves the combination of multidimensional integration of small molecule and protein chemical biology.
