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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. June 2003, Volume 2, Number 6, 403-412 |
Bone Resorption Inhibition Quantitative Structure-Activity
Relationships for Aryl-Substituted Bisphosphonates
Teodora Ivanciuc and Ovidiu Ivanciuc
Internet Electron. J. Mol. Des. 2003, 2, 403-412
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Abstract:
Quantitative structure-activity relationships (QSAR) models
for the bone resorption inhibition of 29 aryl-substituted
bisphosphonates (ABP) were established with the CODESSA
program. The QSAR models for the ABP bone resorption
inhibition are obtained by selecting descriptors from a wide
diversity of constitutional, topological, electrostatic and
quantum structural indices. Standard quantum chemistry
packages are used for optimizing the molecular geometry and
for semi-empirical quantum computations at the AM1 level. A
heuristic algorithm selects the best multiple linear regression
equation according to the highest statistical indices; the
predictive power of each QSAR model is estimated with the
leave-one-out (LOO) cross-validation method. For the whole
set of 29 compounds, the best QSAR model (r2 = 0.8328,
r2LOO = 0.7479,
s2 = 0.251, F = 29.88) is obtained with four quantum
descriptors (minimum total interaction for a C-P bond,
maximum valency of a N atom, minimum total interaction for a
C-C bond, and hydrogen-acceptors surface area). A significant
improvement of the statistical indices is obtained by deleting
three outliers, when a fairly good QSAR is obtained
(r2 = 0.8827, r2LOO = 0.8231,
s2 = 0.118, F = 39.51) also with four
quantum descriptors (minimum electron-electron repulsion for
a H-N bond, minimum coulombic interaction for a C-P bond,
maximum one-electron reactivity index for a N atom, and
minimum total interaction for a H-O bond). These results
demonstrate the ability of AM1 quantum indices in modeling
the bone resorption inhibition of aryl-substituted
bisphosphonates.
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