Identification of non-lipid LPA sub(3) antagonists by virtual screening

In the present study, we utilized virtual screening to identify LPA sub(3) antagonists. We have developed a three-point structure-based pharmacophore model based on known LPA sub(3) antagonists. This model was used to mine the NCI database. Docking, pharmacophore development, and database mining pro...

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Published inBioorganic & medicinal chemistry Vol. 16; no. 11; pp. 6207 - 6217
Main Authors Fells, James I, Tsukahara, Ryoko, Fujiwara, Yuko, Liu, Jianxiong, Perygin, Donna H, Osborne, Daniel A, Tigyi, Gabor, Parrill, Abby L
Format Journal Article
LanguageEnglish
Published 01.06.2008
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Summary:In the present study, we utilized virtual screening to identify LPA sub(3) antagonists. We have developed a three-point structure-based pharmacophore model based on known LPA sub(3) antagonists. This model was used to mine the NCI database. Docking, pharmacophore development, and database mining produced new, non-lipid leads. Experimental testing of seven computationally selected pharmacophore hits produced one potentiator and three antagonists, one of which displays both LPA sub(3) selectivity and nanomolar potency. Similarity searching in the ChemBridge database using the most promising lead as the search target produced four additional LPA sub(3) antagonists and a potent dual LPA sub(1&2) antagonist.
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ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.04.035