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.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Gozalbes R,Mosulén S,Carbajo RJ,Pineda-Lucena Adoi
10.1007/s10822-009-9269-0subject
Has Abstractpub_date
2009-08-01 00:00:00pages
555-69issue
8eissn
0920-654Xissn
1573-4951journal_volume
23pub_type
杂志文章abstract::A set of algorithms designed to enhance the display of protein binding cavities is presented. These algorithms, collectively entitled CAVITY SEARCH, allow the user to isolate and fully define the extent of a particular cavity. Solid modeling techniques are employed to produce a detailed cast of the active site region,...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00117400
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-009-9263-6
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1016320106741
更新日期:2002-02-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00125664
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-012-9601-y
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doi:10.1007/s10822-017-0061-2
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF01532991
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF01531996
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-005-3693-6
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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