Computational model ensemble to assist drug design for the treatment of refractory epilepsy

MELISA E. GANTNER; LUIS E. BRUNO-BLANCH; ALAN TALEVI

Buenos Aires

Congreso; VIII Congreso Latinoamericano de Epilepsia; 2014

International League Against Epilepsy

Objective: Refractory epilepsy has been associated with an overexpression of ABC (ATP-binding cassette) transporters such as P-glycoprotein (Pgp) and Breast Cancer Resistance Protein (BCRP) [1]. A number of reports indicate that BCRP is the most abundantly expressed ABC efflux transporter throughout the intestine [2] and the blood-brain barrier [3,4] of healthy tissues, limiting oral absorption and brain bioavailability of its substrates. Early recognition of BCRP substrates is thus essential to design novel therapeutics for the treatment of refractory epilepsy and other central nervous system conditions linked to BCRP-mediated multidrug resistance issues. Therefore, we present the development of an ensemble of nonlinear computational models capable of discriminating between BCRP substrates and nonsubstrates. Methods: A dataset of 262 substrates and nonsubstrates of BCRP was compiled from literature. J48 decision tree-inducing algorithm was used to obtain independent nonlinear classifiers and the 12 decision trees with the best classification performance were validated and combined using rank average classifier ensemble. Results: According to the computational experiments conducted, the resulting ensemble has the best capacity to discriminate between BCRP substrates and non-substrates. Conclusions: The ensemble developed is a potentially valuable tool to assist the discovery of new drugs for the treatment of refractory epilepsy. References: 1. Nakanishi H, Yonezawa A, Matsubara K, Yano I. Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models. Eur J Pharmacol 2013; 710: 20-8. 2. Tucker TG1, Milne AM, Fournel-Gigleux S, Fenner KS, Coughtrie MW. Absolute immunoquantification of the expression of ABC transporters P-glycoprotein, breast cancer resistance protein and multidrug resistanceassociated protein 2 in human liver and duodenum. Biochem Pharmacol 2012; 83: 279-85. 3. Dauchy S1, Dutheil F, Weaver RJ, Chassoux F, Daumas-Duport C, Couraud PO, et al. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier. J Neurochem 2008; 107: 1518-28. 4. Uchida Y1, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 2011; 117: 333-45.