Abstract
Drugs acting on central nervous system (CNS) may take longer duration to reach the market as these compounds have a higher attrition rate in clinical trials due to the complexity of the brain, side effects, and poor blood–brain barrier (BBB) permeability compared to non-CNS-acting compounds. The roles of active efflux transporters with BBB are still unclear. The aim of the present work was to develop a predictive model for BBB permeability that includes the MRP-1 transporter, which is considered as an active efflux transporter. A support vector machine model was developed for the classification of MRP-1 substrates and non-substrates, which was validated with an external data set and Y-randomization method. An artificial neural network model has been developed to evaluate the role of MRP-1 on BBB permeation. A total of nine descriptors were selected, which included molecular weight, topological polar surface area, ClogP, number of hydrogen bond donors, number of hydrogen bond acceptors, number of rotatable bonds, P-gp, BCRP, and MRP-1 substrate probabilities for model development. We identified 5 molecules that fulfilled all criteria required for passive permeation of BBB, but they all have a low logBB value, which suggested that the molecules were effluxed by the MRP-1 transporter.
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Acknowledgements
Mr. Vilas Belekar acknowledges Department of Electronics and Information Technology, GOI, New Delhi, India, for providing Senior Research Fellowship [Grant File No. DIT/R&D/Bio/15(3)/ 2011]. The authors acknowledge Prof. Inderpal Singh and Mr. Rameshwar Prajapati for their valuable inputs.
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Lingineni, K., Belekar, V., Tangadpalliwar, S.R. et al. The role of multidrug resistance protein (MRP-1) as an active efflux transporter on blood–brain barrier (BBB) permeability. Mol Divers 21, 355–365 (2017). https://doi.org/10.1007/s11030-016-9715-6
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DOI: https://doi.org/10.1007/s11030-016-9715-6