RESUMO
BACKGROUND: During the past decades, an important number of anticonvulsant drugs have been incorporated into the collection of drugs to treat epilepsy. However, two main difficulties remain unsolved in therapy: the development of drug-resistant epilepsy and the occurrence of severe toxic effects caused by the medication in responsive patients. The retrospective analysis of the strategies for discovering known anticonvulsant drugs showed that screening campaigns on animal models of epilepsy have been almost the exclusive strategy for identifying the marketed compounds. However, the actual structural and functional information about the molecular targets of the anticonvulsant drugs and the increasing knowledge of the molecular alterations that generate epileptic seizures allow a more rational identification of active compounds. OBJECTIVE: This review compiles target-based strategies used for the discovery of new anticonvulsant candidates and is divided in two main topics. The first one provides an overview of the computational approaches (docking-based virtual screening and molecular dynamics) to find anticonvulsant structures that interact with the voltage-gated ion channels and the enzyme carbonic anhydrase. The second one includes the analysis of active compounds synthesized to act simultaneously on different molecular targets by the combination of pharmacophores of anticonvulsant drugs. CONCLUSION: Current knowledge of the architectures of anticonvulsant targets makes computational simulations attractive methods for the discovery and optimization of active compounds. Combining the results achieved by virtual screening of different targets could lead to multitarget compounds, as an alternative to the design of structures that merge scaffolds of known drugs.
Assuntos
Anidrases Carbônicas , Epilepsia , Animais , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Humanos , Estudos Retrospectivos , Convulsões/tratamento farmacológicoRESUMO
A set of N,N'-disubstituted sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.1) found in the brain, that is, CA I, CA II, CA VII, CA IX, CA XII and CA XIV, some of which are involved in epileptogenesis. The biological data showed interesting results for CA VII inhibition, the isozyme thought to be a novel antiepileptic target. Strong CA VII inhibitors, with Ki values in the low nanomolar-subnanomolar range were identified. Some of these derivatives showed selectivity for inhibition of CA VII versus the ubiquitous isoform CA II, for which the Ki values were in the micromolar range. Molecular modeling approaches were employed to understand the binding interactions between these compounds and the two CA isoforms, since the mechanism of action of such disubstituted sulfamides was not yet investigated by means of X-ray crystallography.