Discovering new antiepileptic drugs addressing the transporter hypothesis of refractory epilepsy. Structure-based approximations.

PABLO PALESTRO; LUCIANA GAVERNET

Antiepileptic Drug Discovery

Humana Press

Año: 2016; p. 281 - 297

p { margin-bottom: 0.25cm; direction: ltr; color: rgb(0, 0, 10); line-height: 120%; text-align: left; }p.western { font-family: "Calibri",serif; font-size: 11pt; }p.cjk { font-family: "Droid Sans Fallback"; font-size: 11pt; }p.ctl { font-family: "Calibri"; font-size: 11pt; }a:link { color: rgb(0, 0, 255); }Drug resistancerepresents a major obstacle to the success of epilepsy treatments,therefore intense investigations have been carried out to explain itsorigins. One of the most experimentally corroborated theories is thetransporter hypothesis. It proposes that, at least for a subset ofpatients, the failure of the anticonvulsant drugs is caused by theirinability to reach the molecular targets, dueto the regional over-expression or activation of efflux transporters.Among them, P-glycoprotein (P-gp) showed over-activity in drugresistant patients as well probed interactions with knownanticonvulsant drugs. In this chapter we summarized thestructure-based approximations employed to identifysubstrates/inhibitors of the glycoprotein, with special attention indescribing the structural data available of the target and thedocking based simulations. We also pointed out our results regardingthe identification of new anticonvulsant candidates that avoid P-gpinteractions by means a sequential ligand-based and target basedscreening. We concluded that this combined protocol might beeffective for the discovery of new compounds that overcome the drugresistance caused by P-gp.