Structural representations of the NCI Diversity Set II in SMILES format

nd properties of the binding site. Structural representations of the NCI Diversity Set II in SMILES format were obtained from the Developmental Therapeutics Program website. CORINA, via the NCIs Online SMILES Translator and Structure File Generator, was used to generate 3-dimensional coordinates in PDB format from the SMILES-formatted file. 36 of the compounds contained arsenic atoms, which are not supported by AD4 or Vina, so all arsenic atoms were replaced by phosphorus. Individual PDB files were prepared for docking using the prepareligand4.py script from MGLTools 1.5.4, using only the largest non-bonded fragment present. The DUD decoys and ligands for HIV protease were obtained from the DUD website. These mol2-formatted files already contained 3-dimesional coordinates, and were translated to PDB format using Open Babel 2.2.3. Following conversion to PDB format, files containing individual compounds were created, then processed using MGLTools. Inhibition of dietary lipid absorption is an evolving strategy to treat cardiovascular complications of disorders of lipid metabolism. Two commonly used drugs in this class of pharmacological agents, orlistat and ezetimibe improve the serum lipoprotein profiles of patients that are at high risk for acute coronary syndrome, stroke and sudden death, and 5-ROX therefore may be used as an adjuvant or alternative to HMG co-reductase inhibitors for the primary and secondary prevention of these disorders. Although confirmation of the efficacy of this pharmacological approach awaits completion of large clinical trials, the adjuvant use of these compounds is common in patients that do not meet targeted reductions of lipoproteins while taking statins. Given the high prevalence of lipid metabolism disorders it is desirable to identify lead compounds that can be developed into new drugs that inhibit lipid absorption via novel mechanisms. Here we report the utility of using the zebrafish for this purpose. Because of their small size, optical transparency zebrafish larvae are well suited for chemical library screens using fluorescent, histochemical or morphological assays. Indeed, a great advantage of chemical screens in zebrafish is the ability to rapidly assess compound efficacy and toxicity in vivo. Given the high degree of conservation of lipid metabolism in teleost fish and mammals, it is likely that compounds identified in a zebrafish screen will act through comparable mechanisms in mammals. Here we report the results of a pilot screen of a non-biased chemical library through which we identified 7 novel compounds that inhibited the absorption of MEDChem Express 1805787-93-2 fluorescent lipid analogues. We show that compounds identified in the primary screening assay can be rapidly prioritized for testing in mammals using a variety of simple, yet high