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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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