Distributed Drug Discovery (D3) is a multidisciplinary undergraduate approach to identifying molecules that exhibit activity in the treatment of neglected diseases such as malaria, leishmaniasis, and tuberculosis as well as recalcitrant cystic fibrosis (CF) airway infections. D3 seeks to accomplish this task by combining computational chemistry, synthetic chemistry, and biological screening all within an educational framework. Recent reports suggest that D-amino acids are effective in the disassembly and inhibition of bacterial biofilms, which are important for a number of bacterial infections, including those in the CF lung. One of our undergraduate D3 procedures allows the systematic construction of many unnatural amino acids from resin-bound glycine alkylated at the alpha carbon with a wide range of alkylating agents. We utilized chemical drawing software to computationally construct (enumerate) phenylalanine analogs accessible using this synthetic procedure with commercially available substituted benzyl halides. A subset of these enumerated molecules was computationally selected for synthesis based on chemical properties. These compounds were synthesized using simple, solid-phase techniques in an undergraduate organic chemistry laboratory class. The racemic unnatural amino acids were then screened for activity in a biofilm assay. The results show biofilm disruption with phenylalanine derivatives. Analysis of the results reveals a trend between lipophilicity and the degree of biofilm inhibition. These new molecules may lead to an avenue for therapy for those CF individuals suffering with bacterial lung infection. As a part of the undergraduate curriculum, this work provides the first example of D3-linked undergraduate student computational analysis, synthesis, and biological evaluation.

Distributed Drug Discovery (D3), successful integration of D3 components: Undergraduate computational, synthetic, and biological evaluation of phenylalanine derivatives as potential biofilm inhibitors

246th National Meeting (2013)

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