D3 Research

Distributed Drug Discovery (D3): Research integrated with student coursework

Prof. Fuller teaches a ten-week research-based laboratory course, the "majors' lab" section of Introduction to Organic Chemistry III, CHEM033L. Students enrolled in this course (12-18 annually) undertake a research project intended to prepare libraries ofantimicrobial drug candidates, arylopeptoids. This experiment module has recently been published in the Journal of Chemical Education.

What is D3?

The idea of “Distributed Drug Discovery” (D3) was pioneered by Dr. William Scott to address the need to develop drugs for diseases that overwhelmingly afflict populations in developing nations. In the developed world, drug discovery has been fueled by the pharmaceutical industry where economic incentives have financed the expensive equipment and procedures currently required. Unfortunately, because the world burden of disease is disproportionately focused in poor nations, there is no economic incentive for the pharmaceutical industry to discover drugs for diseases of the developing world.

The premise of the D3 concept is that by developing simple, inexpensive equipment and procedures for each of the core drug discovery scientific disciplines (computational chemistry, synthetic chemistry and biochemical screening), large research problems can be broken down into manageable smaller units and carried out at multiple academic sites throughout the developing and developed world. The coordinated and recombined results of these “distributed” resources will inexpensively accelerate the identification of leads in the early stages of the drug discovery process. Additionally this “distributed discovery” effort will provide educational and job opportunities in both the developed and developing worlds while building cultural and economic bridges for the common good.

D3 projects at SCU: Synthesis of arylopeptoid libraries

Our inspiration for the molecular design of drug-like molecules comes from nature. Antimicrobial peptides (AMPs) are short peptides (usually 10-50 amino acids) isolated from natural sources that kill bacteria and other pathogens by disrupting their cell membranes. AMPs bear both positively charged and hydrophobic side chains, giving them an “amphiphilic” structure that is essential for antimicrobial function: one face of the molecule is positively charged and the other face of the molecule is hydrophobic. A number of different oligoamide molecular scaffolds have been shown to be effective antimicrobials.

For this laboratory course, we have chosen to prepare and characterize arylopeptoids as AMP mimics because

1) They can be engineered to be amphiphilic.

2) Molecules can be diversely functionalized at various parts of the structure via combinatorial chemistry.

3) They are easy to make using readily available, inexpensive materials and equipment.

Our scheme for the synthesis of these molecules and the synthetic building blocks we use are shown below:

SCU organic chemistry students interested in enrolling in the majors' lab section of CHEM033 should contact Prof. Fuller prior to the start of the spring quarter. Enrollment priority is given to chemistry and biochemistry majors.

If you are interested in learning more about implementing D3 experiments in your own curriculum, please see the references below, other materials posted on this website, and/or contact Prof. Fuller or Prof. Bill Scott (IUPUI).

key references:

For more information on D3, please see the following references:

Scott, W. L., et al "Distributed Drug Discovery: Advancing Chemical Education through Contextualized Combinatorial Solid-Phase Organic Laboratories." J. Chem. Educ. 2015, 92, 819-826.

Scott, W. L.; O'Donnell, M. J. "Distributed Drug Discovery, Part 1: Linking Academia and Combinatorial Chemistry to Find Drug Leads for Developing World Diseases" J. Comb. Chem. 2009, 11, 3-13. (Free access to this paper)

Scott, W. L., et al "Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D3 Catalog Construction." J. Comb. Chem. 2009, 11, 14-33. (Free access to this paper)

Scott, W. L., et al "Distributed Drug Discovery, Part 3: Using D3 Methodology to Synthesize Analogs of an Anti-Melanoma Compound" J. Comb. Chem. 2009, 11, 3-13. (Free access to this paper)

Also see this editorial in J. Comb. Chem. on D3

For more information on arylopeptoid synthesis, please see these references:

Hjelmgaard, T.; Faure, S.; De Santis, E.; Staerk, D.; Alexander, B. D.; Edwards, A. A.; Taillefumier, C.; Nielsen, J. "Improved solid-phase synthesis and study of arylopeptoids with conformation-directing side chains" Tetrahedron 2012, 68, 4444.

Hjelmgaard, T.; Faure, S.; Staerk, D.; Taillefumier, C.; Nielsen, J. "Efficient and versatile COMU-mediated solid-phase submonomer synthesis of arylopeptoids (oligomeric N-substituted aminomethyl benzamides)" Org. Biomol. Chem. 2011, 9, 6832.

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