Discovering New Antiepileptic Drugs Addressing the Transporter Hypothesis of Refractory Epilepsy: Ligand- Based Approximations

Abstract

Drug resistance represents a major obstacle to the success of epilepsy treatments, therefore intense investigations have been carried out to explain its origins. One of the most experimentally corroborated theories is the transporter hypothesis. It proposes that, at least for a subset of patients, the failure of the anticonvulsant drugs is caused by their inability to reach the molecular targets, due to the regional over-expression or activation of efflux transporters. Among them, P-glycoprotein (P-gp) showed over-activity in drug resistant patients as well as probed interactions with known anticonvulsant drugs. In this chapter we summarized the structure-based approximations employed to identify substrates/inhibitors of the glycoprotein, with special attention in describing the structural data available of the target and the docking based simulations. We also pointed out our results regarding the identification of new anticonvulsant candidates that avoid P-gp interactions by means a sequential ligand-based and target-based screening, along with practical details related to this protocol.