About D3

IUPUI D3 Workshop Thumbnailworkshop participant map

OVERVIEW

D3 integrates education with computational analysis, organic synthesis and biological evaluation to create an open-access network providing drug leads for neglected diseases.  It relies on simple, inexpensive and powerful methodologies to break large drug discovery problems into smaller, manageable units that can be solved in a globally distributed process. Students involved in this project learn key skills while seeing them applied to critical needs, providing a rich setting for contextualized learning. We described the concept of D3 in the Journal of Combinatorial Chemistry (Scott, W. L.; O’Donnell, M. J. Distributed Drug Discovery, Part 1: Linking Academics and Combinatorial Chemistry to Find Drugs for Developing World Diseases. J. Comb. Chem. 2009, 11, 3-13). In subsequent articles (J. Comb. Chem. 2009, 11, 14-33; J. Comb. Chem. 2009, 11, 34-43) we present specific examples of how the distributed synthetic chemistry component is being carried out in labs across the world. Efforts toward improving and expanding D3 chemistry are ongoing (J. Org. Chem. 2014, 79, 3140-3151). Distributed computational analysis and distributed biological evaluation of these molecules (in order to identify drug leads for neglected diseases) are still in the earlier stages but are making significant strides forward. Since our 2009 publications we’ve received NSF funding for a D3 project entitled “Advancing Undergraduate Chemical Education through Contextualized Organic Laboratories” (NSF/DUE-1140602, May 2012-May 2015).

OUTCOMES

We have submitted student made compounds to the NIH small molecule repository, some of which have been reported to be active in NIH sponsored screens (e.g. oxytocin, leishmania, and malaria). One of the student-made compounds turned out to have a structure only an isopropyl group away from a marketed drug. This more than validates the "drug like" nature of student accessible compounds in our D3 virtual catalogs. Reproducibility of student work is a fundamental value in D3. Synthetically, our students have made over 700 unique compounds in their undergraduate labs. All of them are made in replicate, sometimes quadruplicate, by separate individuals. This guarantees reproducibility and access to future scale-up. Most of the crude products are greater than 80% pure as judged by LC/MS with UV detection. Our students have purified a subset of these but purification of all of them to >90-95% purity is a practical challenge so we hope to postpone that purification until preliminary activity is found in the unpurified (but > 80% pure) samples. The state of purity required for screening is up for discussion. Most of our compounds are racemates. We believe this is an efficient way to perform the initial hit screening process, with follow-up work on individual enantiomers (either through synthesis or chiral chromatography/resolution) when data looks promising. We have at least five "D3 certified" synthetic procedures that have been successfully run in undergrad labs. Analogous computation and biology labs are undergoing optimizations. One of our specialties is the synthesis of N-acylated unnatural amino acids. All D3 procedures are compatible with both solid-phase synthesis and combinatorial chemistry. A subset of the virtual catalogs (containing over 70,000 compounds) has been made publicly and freely available through Collaborative Drug Discovery (CDD) (sign up for a free account and explore data to see our free IUPUI molecular libraries).

D3 COMMUNITY

We are especially looking for external collaborators to help us develop new education modules to 1) identify interesting molecules for neglected diseases, 2) test molecules in neglected disease screens, and 3) develop new chemistry to expand the molecules accessible through D3 student-enabled procedures. There is an educational initiative in the Computational Division of the American Chemical Society called “TDT” for Teach-Discover-Treat. We are collaborating with them and hope to utilize student compatible educational computational packages, coming from the TDT program, to allow students to analyze our D3 catalogs for the selection of appropriate candidates for synthesis and testing against neglected diseases. As part of the broader D3 initiative and concept, we are developing, both internally and externally, parallel biological screens to enable undergraduate students to be trained in, and participate in, evaluation of student-made compounds as potential drug leads. A growing community (see the 2013 Inaugural Distributed Drug Discovery Workshop photo above) is making progress toward a fully distributed drug discovery process. At that workshop there were representatives from Poland, Czech Republic and Kenya, as well as schools large and small across the US. We now have D3 collaborations with over 10 schools nationally and internationally. We have national and international involvement in the project as demonstrated by the International D3 workshop we conducted last summer. We recently gave 8 presentations (4 oral & 4 poster) at the fall 2013 ACS National Meeting in Indianapolis and will be conducting a workshop on D3 at a Biennial Conference on Chemical Education (BCCE) this August at Grand Valley State University. We recently gave 8 presentations (4 oral & 4 poster) at the fall 2013 ACS National Meeting in Indianapolis and will be conducting a workshop on D3 at a Biennial Conference on Chemical Education (BCCE) this August.

We are always looking to add more interested educators and scientists.  For all interested, we suggest a D3 adoption timeline.  Contact us to learn more.