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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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