The broader impact/commercialization potential of this Small Business Innovation Research (SBIR) Phase I project is to enable drug discovery for life-threatening diseases. A group of proteins involved in cancers and neurodegenerative disorders, as well as many proteins inside bacteria and viruses, are desirable therapeutic targets due to their role in disease. Designing therapeutics to regulate these proteins is difficult because of their challenging structural features. Specifically, these proteins constantly shift shapes instead of remaining rigid like existing therapeutic targets. This project aims to develop a computational-experimental platform to facilitate the discovery of therapeutics for shape-shifting proteins. This Small Business Innovation Research (SBIR) Phase I project facilitates structure-based drug discovery for intrinsically disordered proteins (IDPs), a class of flexible proteins implicated in life-threatening diseases. The extreme flexibility of IDPs enables their diverse cellular functions, but obscures experimental details about their conformations. Because of this, traditional drug discovery methods have lacked the structural details needed to design and optimize ligands that regulate IDPs, and no drugs have been successfully developed that target IDPs. The first aim of this project is to develop an AI-chemistry-based molecular dynamics algorithm for accurately modeling conformations adopted by a given IDP. In the second aim, these structural models will be coupled with NMR fragment screens in order to obtain detailed models of the interactions between the proof-of-concept IDP and any small molecule fragments observed to bind the IDP. In the third aim, the structural models will direct the fusion, extension, and optimization of promising fragments to design lead candidates for regulating the proof-of-concept IDP, and biophysical experiments will validate and guide computational hypotheses. Together, these aims provide a systematic platform for structure-based drug discovery for IDPs, as well as a set of lead candidates for targeting the proof-of-concept protein.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
