Development and NMR validation of minimal pharmacophore hypotheses for the generation of fragment libraries enriched in heparanase inhibitors |
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Authors: | Rafael Gozalbes Silvia Mosulén Rodrigo J Carbajo Antonio Pineda-Lucena |
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Institution: | (1) Structural Biology Laboratory, Department of Medicinal Chemistry, Centro de Investigación Príncipe Felipe, Avenida Autopista del Saler 16, 46012 Valencia, Spain |
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Abstract: | A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification
of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and
subendothelial basement membranes, resulting in the dissemination of metastatic cancer cells. Several pharmacophore hypotheses
were initially developed from the most active heparanase inhibitors known to date and, after their application to a pool of
27 known heparanase inhibitors and a database of 1,120 compounds approved by the FDA, a four-point pharmacophore model was
selected as the most predictive. This model was subsequently applied to a database of 686 chemical fragments, and a subset
of 100 fragments accomplishing completely or partially the four-point model was selected to perform nuclear magnetic resonance
experiments to validate the hypothesis. The experimental studies confirmed the reliability of our pharmacophore model, its
applicability to in silico databases in order to reduce the number of compounds to be experimentally screened, and the possibility
of generating fragment libraries enriched in heparanase inhibitors.
Rafael Gozalbes and Silvia Mosulén contributed equally to this work. |
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Keywords: | Pharmacophore Fragment-based screening NMR Heparanase Inhibitor |
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