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Two- and three-dimensional quantitative structure–permeability relationship of flavonoids in Caco-2 cells using stepwise multiple linear regression (SMLR), partial least squares regression (PLSR), and pharmacophore (GALAHAD)-based comparative molecular similarity index analysis (COMSIA)

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Abstract

Limited oral bioavailability has hindered the widespread use of flavonoids as bioactive substances. Several studies have been performed to evaluate the transport characteristics of flavonoids in the intestines using cell models, such as Caco-2 cells, but information regarding the key structural features of flavonoids that influence intestinal uptake is still limited to date. In this study, quantitative structure–permeability relationship (QSPR) models were developed to study the permeability of 36 flavonoids through Caco-2 cells using both 2D and 3D approaches. For the 2D model, stepwise multiple linear regression (SMLR) and partial least squares regression (PLSR) resulted in good internal (R 2SMLR  = 0.8, R 2PLSR  = 0.93) and external (R 2SMLR  = 0.93, R 2PLSR  = 0.90) predictability using a set of 409 molecular descriptors. The high cross-validated (leave-one-out) R 2 values (Q 2) for both 2D models (Q 2SMLR  = 0.77, Q 2PLSR  = 0.67) suggest that the models are robust and predictive. A pharmacophore (GALAHAD)-based COMSIA analysis was used to generate the 3D QSPR model, which yielded a predictive and robust model (R 2training  = 0.96, R 2test  = 0.95, Q 2 = 0.625) composed of hydrogen bond acceptor and donor fields. According to the contour plots, the locations of hydrogen bond acceptors and donors play a crucial role in determining Caco-2 permeability of flavonoids. The models provide deeper insight into the QSPR of flavonoids on intestinal absorption using Caco-2 cell models and could be useful for the high-throughput screening of flavonoids and/or flavonoid-like drugs with health-promoting activities.

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Acknowledgments

The authors would like to thank the Special Research Fund (BOF) of the Ghent University for the financial support.

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Authors and Affiliations

  1. Department of Food Safety and Food Quality, Faculty of Bioscience Engineering, Ghent University, 9000, Ghent, Belgium

    Gerard Bryan Gonzales, John Van Camp & Charlotte Grootaert

  2. Department of Industrial Biological Science, Faculty of Bioscience Engineering, Ghent University, 8500, Kortrijk, Belgium

    Gerard Bryan Gonzales & Katleen Raes

  3. Department of Crop Protection, Faculty of Bioscience Engineering, Ghent University, 9000, Ghent, Belgium

    Gerard Bryan Gonzales, Moises Zotti & Guy Smagghe

  4. Department of Crop Protection, Laboratory of ChemoGenomics and Bioinformatics, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Moises Zotti

  5. Department of Mathematics, Physics and Computer Sciences, College of Science and Mathematics, University of the Philippines Mindanao, 8000, Mintal Davao, Philippines

    Vladimer Kobayashi

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  1. Gerard Bryan Gonzales
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  2. John Van Camp
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  3. Moises Zotti
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  4. Vladimer Kobayashi
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Correspondence to Guy Smagghe.

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Gonzales, G.B., Van Camp, J., Zotti, M. et al. Two- and three-dimensional quantitative structure–permeability relationship of flavonoids in Caco-2 cells using stepwise multiple linear regression (SMLR), partial least squares regression (PLSR), and pharmacophore (GALAHAD)-based comparative molecular similarity index analysis (COMSIA). Med Chem Res 24, 1696–1706 (2015). https://doi.org/10.1007/s00044-014-1241-4

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