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Int. J. Mol. Sci. 2012, 13(4), 5138-5162; doi:10.3390/ijms13045138

Identification of Important Chemical Features of 11β-Hydroxysteroid Dehydrogenase Type1 Inhibitors: Application of Ligand Based Virtual Screening and Density Functional Theory

1
Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju, 660-701, Korea
2
Department of Physics (FEAT), Annamalai University, Annamalainagar 608 002, Tamil Nadu, India
*
Author to whom correspondence should be addressed.
Received: 30 January 2012 / Revised: 19 March 2012 / Accepted: 5 April 2012 / Published: 23 April 2012

Abstract

11ß-Hydroxysteroid dehydrogenase type1 (11ßHSD1) regulates the conversion from inactive cortisone to active cortisol. Increased cortisol results in diabetes, hence quelling the activity of 11ßHSD1 has been thought of as an effective approach for the treatment of diabetes. Quantitative hypotheses were developed and validated to identify the critical chemical features with reliable geometric constraints that contribute to the inhibition of 11ßHSD1 function. The best hypothesis, Hypo1, which contains one-HBA; one-Hy-Ali, and two-RA features, was validated using Fischer’s randomization method, a test and a decoy set. The well validated, Hypo1, was used as 3D query to perform a virtual screening of three different chemical databases. Compounds selected by Hypo1 in the virtual screening were filtered by applying Lipinski’s rule of five, ADMET, and molecular docking. Finally, five hit compounds were selected as virtual novel hit molecules for 11ßHSD1 based on their electronic properties calculated by Density functional theory. View Full-Text
Keywords: 11β-hydroxysteroid dehydrogenase; pharmacophore; density function theory; molecular docking; diabetes; virtual screening 11β-hydroxysteroid dehydrogenase; pharmacophore; density function theory; molecular docking; diabetes; virtual screening
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MDPI and ACS Style

Sakkiah, S.; Meganathan, C.; Sohn, Y.-S.; Namadevan, S.; Lee, K.W. Identification of Important Chemical Features of 11β-Hydroxysteroid Dehydrogenase Type1 Inhibitors: Application of Ligand Based Virtual Screening and Density Functional Theory. Int. J. Mol. Sci. 2012, 13, 5138-5162.

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