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J Comput Chem. 2011 Feb;32(3):463-82. doi: 10.1002/jcc.21635. Epub 2010 Aug 20.

Discovery of new β-D-galactosidase inhibitors via pharmacophore modeling and QSAR analysis followed by in silico screening.

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1
Department of Chemistry, Faculty of Science, University of Jordan, Amman, Jordan.

Abstract

Glycosidases, including β-D-galactosidase, are involved in a variety of metabolic disorders, such as diabetes, viral or bacterial infections, and cancer. Accordingly, we were prompted to find new β-D-galactosidase inhibitors. Towards this end, we scanned the pharmacophoric space of this enzyme using a set of 41 known inhibitors. Genetic algorithm and multiple linear regression analyses were used to select an optimal combination of pharmacophoric models and physicochemical descriptors to yield self-consistent and predictive quantitative structure-activity relationship (QSAR). Five pharmacophores emerged in the QSAR equations suggesting the existence of more than one binding mode accessible to ligands within β-D-galactosidase pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic curve profiles. The validity of the QSAR equations and the associated pharmacophoric models were experimentally established by the identification of several β-D-galactosidase inhibitors retrieved via in silico search of two structural databases: the National Cancer Institute list of compounds and our in house built structural database of established drugs and agrochemicals.

PMID:
20730780
DOI:
10.1002/jcc.21635
[Indexed for MEDLINE]

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