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Predicting PAMPA permeability using the 3D-RISM-KH theory: are we there yet?

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Abstract

The parallel artificial membrane permeability assay (PAMPA), a non-cellular lab-based assay, is extensively used to measure the permeability of pharmaceutical compounds. PAMPA experiments provide a working mimic of a molecule passing through cells and PAMPA values are widely used to estimate drug absorption parameters. There is an increased interest in developing computational methods to predict PAMPA permeability values. We developed an in silico model to predict the permeability of compounds based on the PAMPA assay. We used the three-dimensional reference interaction site model (3D-RISM) theory with the Kovalenko–Hirata (KH) closure to calculate the excess chemical potentials of a large set of compounds and predicted their apparent permeability with good accuracy (mean absolute error or MAE = 0.69 units) when compared to a published experimental data set. Furthermore, our in silico PAMPA protocol performed very well in the binary prediction of 288 compounds as being permeable or impermeable (precision = 94%, accuracy = 93%). This suggests that our in silico protocol can mimic the PAMPA assay and could aid in the rapid discovery or screening of potentially therapeutic drug leads that can be delivered to a desired tissue.

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Acknowledgements

This work was financially supported by the NSERC Discovery Grant (RES0029477), Alberta Innovates AARP VII Research Grant (RES0043948), and Alzheimer Society of Alberta and Northwest Territories AARP VII Research Grant (RES0043949). Generous computing time provided by WestGrid (www.westgrid.ca) and Compute Canada/Calcul Canada (www.computecanada.ca) is acknowledged. The authors thank Dr. Marcia LeVatte for assistance in editing the manuscript.

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Authors and Affiliations

  1. Department of Mechanical Engineering, University of Alberta, 10-203 Donadeo Innovation Centre for Engineering, 9211-116 Street NW, Edmonton, AB, T6G 1H9, Canada

    Dipankar Roy & Andriy Kovalenko

  2. Departments of Biological Sciences and Computing Science, University of Alberta, Edmonton, AB, T6G 2E8, Canada

    Devjyoti Dutta & David S. Wishart

  3. Nanotechnology Research Centre, National Research Council of Canada, 11421 Saskatchewan Drive, Edmonton, AB, T6G 2M9, Canada

    Andriy Kovalenko

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  1. Dipankar Roy
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All the authors contributed equally to writing the manuscript and approved the final version.

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Correspondence to Andriy Kovalenko.

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Roy, D., Dutta, D., Wishart, D.S. et al. Predicting PAMPA permeability using the 3D-RISM-KH theory: are we there yet?. J Comput Aided Mol Des 35, 261–269 (2021). https://doi.org/10.1007/s10822-020-00364-4

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