Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs

Virtual molecular catalogs have limited utility if member compounds are (i) difficult to synthesize or (ii) unlikely to have biological activity. The Distributed Drug Discovery (D3) program addresses the synthesis challenge by providing scientists with a free virtual D3 catalog of 73,024 easy-to-synthesize N-acyl unnatural α-amino acids, their methyl esters, and primary amides. The remaining challenge is to document and exploit the bioactivity potential of these compounds. In the current work, a search process is described that retrospectively identifies all virtual D3 compounds classified as bioactive hits in PubChem-cataloged experimental assays. The results provide insight into the broad range of drug-target classes amenable to inhibition and/or agonism by D3-accessible molecules. To encourage computer-aided drug discovery centered on these compounds, a publicly available virtual database of D3 molecules prepared for use with popular computer docking programs is also presented

Successful Integration of Distributed Drug Discovery (D3) Components: Computational, Synthetic, and Biological Evaluation of Phenylalanine Derivatives as Potential Biofilm Inhibitors

poster abstractDistributed Drug Discovery (D3) is a multidisciplinary 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. Utilizing chemical drawing software, we constructed (enumerated) target phenylalanine derivatives from commercially available benzyl halides by substitution at the α position of an amino acid scaffold. 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 resulting racemic unnatural amino acid derivatives were then screened for activity in a biofilm assay. The results show biofilm inhibition with synthesized 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

Hydroxychloroquine dimers as inhibitors of Plasmodium falciparum chloroquine resistant transporter and P-glycoprotein

Plasmodium falciparum chloroquine resistance transporter (PfCRT) and P-glycoprotein (P-gp) are efflux proteins that are responsible for multi-drug resistance. The mutations in the protein PfCRT, which is present in malarial parasites, leads to the efflux of antimalarials, like aminoquinolines which leads to resistance. P-gp, a mammalian protein, recognizes a wide variety of drugs and effluxes them out of cells, thereby leading to multi-drug resistance and the inability to treat diseases efficiently. The bivalent strategy has been developed by using substrates of these proteins as starting materials to develop bivalent inhibitors. In this way, a set of quinine dimers has been found to be successful in inhibiting PfCRT CQR, while exhibiting antiplasmodial activity. Also a library of hydroxychloroquine dimers showed tether length dependence on the inhibition of PfCRTCQR . Herein is described a more extensive set of hydroxychloroquine dimers that was synthesized to fill the gaps in the original library. These compounds will be tested against PfCRT in collaboration with Dr. Rowena Martin. The hydroxychloroquine dimers were also tested for P-gp inhibition. Potent inhibition of substrate efflux was observed with the short tethered dimers showing better inhibition than the longer tethered dimers