Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos

Abstract

Epilepsy is a disease characterized by the recurrent presence of seizures, with the neurobiological, cognitive, psychological, and social consequences that this implies. It affects more than 50 million people worldwide, which makes it the second most common neurological disease globally. The vast majority of those affected live in low-income countries and as a consequence, nearly 75% of them do not receive appropriate treatment. Pharmacotherapy is the first-line treatment for this pathology. However, approximately 30% of patients do not respond to existing pharmacological therapies. This motivates the constant search for safer and better-tolerated anticonvulsant drugs (ACDs) that overcome the drug resistance problem. In this regard, this doctoral thesis aims to find multitarget compounds that act simultaneously on TRPV1 and NaV1.2 channels, with potential anticonvulsant activity in vivo, through a computer-aided drug repositioning strategy. For both molecular targets ligand- (QSAR) and structure-based (docking and molecular dynamics) predictive models were developed. The ensemble of models was applied in a virtual screening campaign over the DrugBank database, aiming to repurpose already approved drugs as ACDs, and three candidates were selected for experimental testing: Montelukast, Novobiocin, and Cinnarizine. All of them demonstrated a potent inhibitory activity on both targets, measured by the patch clamp technique on a heterologous expression system in HEK293 cells. Additionally, the candidates were tested in four animal models of seizures: MES, 6-hz, PTZ, and GASH:Sal. All drugs exhibited anticonvulsant activity in at least one of these models, and none of them showed signs of neurotoxicity in the Rotorod test. The combination of in silico methodologies, based on the structure of the ligands and the receptor, proved to be a useful approach for the identification of multitarget compounds in the context of a disease such as Epilepsy. Moreover, the joint modulation of TRPV1 and NaV1.2 channels emerge as a promising strategy for the development of novel ACDs.