COMPUTER ASSISTED EARLY IDENTIFICATION OF PGP-SUBSTRATES AND NON-SUBSTRATES AS A STRATEGY FOR THE DESIGN OF NEW DRUGS FOR THE TREATMENT OF REFRACTORY EPILEPSY

MAURICIO E. DI IANNI; ANDREA ENRIQUE; ALAN TALEVI; LUIS E. BRUNO-BLANCH

Alejandría

Conferencia; TWAS/BioVisionAlexandria Nxt.2012 International Biennial Conference; 2012

Center for Special Studies and Programs (CSSP) y TWAS Arab Regional Office (TWAS-ARO)

P-glycoprotein (Pgp) is one of the major efflux transporters associated to multi-drug resistance issues (i.e. inability of a wide-range of unrelated drugs to control disease progression and/or symptoms) in a number of health conditions, such as epilepsy, cancer and HIV. Therefore, early recognition of Pgp substrates is an important step in the drug design process in order to develop novel therapies capable of overcoming Pgp-mediated multi-drug resistance issues [1,2]. In our case, we are interested in the development of novel anticonvulsant treatments capable of controlling refractory (or intractable) epilepsy, which affects around one third of the antiepileptic patients [3]. We have developed a highly specific ensemble of topological models capable of differentiating a Pgp-substrate from a non-substrate [4]. This ensemble has been applied to select drug candidates for the treatment of refractory epilepsy from a large virtual repository of small organic drug-like molecules (ZINC database). We have selected a first series of six candidates that are being pharmacologically tested in preclinical animal models of epilepsy. Two of them hydroxycycloheptane-1-carboxylic acid and 7,7 dimethylbicyclo [2.2.1]heptane-1-carboxamide have already shown to be effective to protect from seizures in an animal model of epilepsy: the Maximal Electroshock test, at the minimal doses stipulated by the NIH Anticonvulsant Drug Development Program.