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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
ABSTRACT - Internet Electron. J. Mol. Des. November 2008, Volume 7, Number 11, 234-250

QSAR Study On Some Orally Active Uracil Derivatives as Human Gonadotropin-Releasing-Hormone Receptor Antagonists
Tarun Jha, Soma Samanta, Soumya Basu, Amit Kumar Halder, Nilanjan Adhikari, and Milan Kumar Maiti
Internet Electron. J. Mol. Des. 2008, 7, 234-250

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Abstract:
Antagonism of human gonadotropin-hormon-releasing receptor (hGnRH-R) using peptide antagonists is a way to treat a variety of sex-hormone-dependent diseases. However, low bioavailability of these peptide antagonists intensifies the need for some orally active small molecules, which may act as hGnRH-R antagonists. To find more active compounds, QSAR study was performed on some orally active substituted uracil derivatives. A QSAR study of 32 derivatives of orally active substituted uracils was done using topological and quantum chemical descriptors. Correlation and multiple regression analyses were performed to develop QSAR models. Results show that the importance of ETSA and RTSA indices of two particular atoms. ETSA index of the atom number 17 and RTSA index of the atom number 19 are important because these atoms may involve in electronic interaction and van der Waals interaction with the receptor respectively. The study also shows the importance of average atomic charges of atom numbers 1, 2, 3, 4, 5, 6 and 9. It suggests the importance of approximate surface area in biological activity. Frontier electron density for electrophilic attack at atom number 24 is also found to be useful for the small molecular antagonism towards the receptor. The pharmacophoric requirement for the substituted uracil derivatives for their human GnRH-R antagonism is illustrated optimally by two tetravariate QSAR models. These models show that compounds with reduced surface area, higher atomic charge and lower electrophilic attack at the atom number 24 may have an increased binding affinity towards hGnRH receptor.

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