Abstract
Aim:
To use membrane-interaction quantitative structure-activity relationship analysis (MI-QSAR) to develop predictive models of partitioning of organic compounds in gastrointestinal cells.
Methods:
A training set of 22 structurally diverse compounds, whose apparent permeability accross cellular membranes of Madin-Darby canine kidney (MDCK) cells were measured, were used to construct MIQSAR models. Molecular dynamic simulations were used to determine the explicit interaction of each test compound (solute) with a dimyristoyl-phosphatidyl-choline monolayer membrane model. An additional set of intra molecular solute descriptors were computed and considered in the trial pool of descriptors for building MI-QSAR models. The QSAR models were optimized using multidimensional linear regression fitting and the stepwise method. A test set of 8 compounds were evaluated using the MI-QSAR models as part of a validation process.
Results:
MI-QSAR models of the gastrointestinal absorption process were constructed. The descriptors found in the best MI-QSAR models are as follows: 1) ClogP (the logarithm of the 1-octanol/water partition coefficient); 2) EHOMO (the highest occupied molecular orbital energy); 3) Es (stretch energy); 4) PMY (the principal moment of inertia Y, the inertia along the y axis in the rectangular coordinates; 5) Ct (total connectivity); and 6) Enb (the energy of interactions between all of the non-bonded atoms). The most important descriptor in the models is ClogP.
Conclusion:
Permeability is not only determined by the properties of drug molecules, but is also very much influenced by the molecule-membrane interaction process.
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Project supported by the National Natural Science Foundation of China (No 30171094 and No 30271497).
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Chen, Ll., Yao, J., Yang, Jb. et al. Predicting MDCK cell permeation coefficients of organic molecules using membrane-interaction QSAR analysis. Acta Pharmacol Sin 26, 1322–1333 (2005). https://doi.org/10.1111/j.1745-7254.2005.00166.x
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DOI: https://doi.org/10.1111/j.1745-7254.2005.00166.x
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