Predicting MDCK cell permeation coefficients of organic molecules using membrane-interaction QSAR analysis

Li Li Chen, Jia Yao, Jian Bo Yang, Jie Yang

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 MI-QSAR 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 intramolecular 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.

Original languageEnglish (US)
Pages (from-to)1322-1333
Number of pages12
JournalActa Pharmacologica Sinica
Issue number11
StatePublished - Nov 2005
Externally publishedYes


  • Artificial membranes
  • Cell membrane permeability
  • MDCK cells
  • Molecular models
  • Organic chemicals
  • Quantitative structure-activity relationship

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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