Molecular Diversity

, Volume 18, Issue 3, pp 599–610 | Cite as

Analysis of structure-Caco-2 permeability relationships using a property landscape approach

  • Yareli Rojas-Aguirre
  • José L. Medina-FrancoEmail author
Full-Length Paper


Understanding the relationship between the chemical structure of bioactive compounds and Caco-2 permeability is of major importance in modern drug discovery. The purpose of this work was to characterize systematically the Caco-2 permeability landscape of a benchmark dataset of 100 molecules using a novel approach based on the emerging concept of property landscape modeling. Pairwise comparisons of the Caco-2 permeability and chemical structures were calculated for all possible combinations in the dataset. To compare the chemical structures, two distinct manners to represent the molecules were employed, namely, continuous properties previously used to derive QSPR models and molecular fingerprints with different designs. We introduce the concept of “permeability cliffs” discussing cases of compounds with high molecular similarity but large permeability difference. All permeability cliffs were regarded as shallow cliffs, since no extreme difference in Caco-2 permeability (less than two log units) was identified in the dataset. A clear dependence of Caco-2 permeability landscape with molecular representation was observed. The current approach can be further extended to model other ADME relevant landscapes.


ADME Caco-2 permeability landscape Permeability cliffs Property landscape Structure-property relationships  



Absorption, distribution, metabolism, and excretion


Caco-2 permeability difference

log D

Experimental distribution coefficient


Molecular ACCess System


Graph \(\pi \)-donor-acceptor-polar-hydrophobe triangle


High-charged polar surface area


Molecular Operating Environment


Fraction of rotatable bonds


Quantitative-structure-activity relationship


Radius of gyration


Structure-activity similarity


Structure-property relationships


Structure-property similarity


Typed graph triangle.



The authors thank Jacob Waddell for writing scripts used to generate the SPS maps.

Supplementary material

11030_2014_9514_MOESM1_ESM.pdf (193 kb)
Supplementary material 1 (PDF 192 kb)
11030_2014_9514_MOESM2_ESM.doc (48 kb)
Supplementary material 2 (DOC 48 kb)
11030_2014_9514_MOESM3_ESM.doc (28 kb)
Supplementary material 3 (DOC 28 kb)
11030_2014_9514_MOESM4_ESM.xlsx (28 kb)
Supplementary material 4 (XLSX 27 kb)
11030_2014_9514_MOESM5_ESM.doc (48 kb)
Supplementary material 5 (DOC 48 kb)
11030_2014_9514_MOESM6_ESM.doc (29 kb)
Supplementary material 6 (DOC 29 kb)


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Yareli Rojas-Aguirre
    • 1
    • 2
  • José L. Medina-Franco
    • 1
    • 3
    Email author
  1. 1.Instituto de QuímicaUniversidad Nacional Autónoma de MéxicoMexico CityMexico
  2. 2.University of MichiganAnn ArborUSA
  3. 3.Mayo ClinicScottsdaleUSA

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