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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. February 2006, Volume 5, Number 2, 60-78 |
Impact of Molecular Hydrophobic Field on Passive Diffusion, P-Glycoprotein Active
Efflux, and P-Glycoprotein Modulation of Steroids
Yan Li, Yonghua Wang, Ling Yang, Shuwei Zhang, and Changhou Liu
Internet Electron. J. Mol. Des. 2006, 5, 60-78
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Abstract:
Passive diffusion is the most common process that drugs undergo
when penetrating the bilayer membrane. However, the extra
involvement of P-glycoprotein (P-gp) always results in the active
efflux of drugs out of the cells. Steroids are a class of compounds
that possess various pharmacological functions that are essential to
human health, and some steroids can be either P-gp substrates
and/or inhibitors. To determine the main structural features of
steroid-based drugs affecting their permeation effects by simply
passive diffusion, or by at the mean time P-gp-mediated active
efflux, as well as the permeation effect when steroids are P-gp
inhibitors, three different datasets were studied by QSAR methods
respectively. And the contributions and distributions of molecular
hydrophobic field, an important hydrophobicity descriptor, to the
three different permeation processes were analyzed and compared
with those of ClogP, another hydrophobicity descriptor.
Comparative molecular similarity index analysis (CoMSIA) was
applied to the three datasets. All developed models exhibited
statistically satisfactory results, with their predictability validated
by test sets independent of training ones. Our findings are that the
contributions of hydrophobic field and ClogP to three different
processes are totally distinct, and the hydrophobic field in 3D-space
distribution correlates better with the potency of a steroid
molecule to passively diffuse or be actively transported by P-gp, or
modulate P-gp-mediated drug efflux. The comparison of different
hydrophobic field contour plots in different models was also
conducted, which is useful for further steroid-based drug design.
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