Computational and Synthetic Target-Based Approaches to the Discovery of Novel Anticonvulsant Compounds

GANTNER, MELISA EDITH; LLANOS, MANUEL AUGUSTO; GAROFALO, FEDERICO MARIANO; VILLALBA, MARÍA LUISA; GAVERNET, LUCIANA

CURRENT MEDICINAL CHEMISTRY.

BENTHAM SCIENCE PUBL LTD

Año: 2021 vol. 28

0929-8673

been incorporated into the collection of drugs to treat epilepsy. However, twomain difficulties remain unsolved in therapy: the development of drug-resistant epilepsyand the occurrence of severe toxic effects caused by the medication in responsive patients.The retrospective analysis of the strategies for discovering known anticonvulsantdrugs showed that screening campaigns on animal models of epilepsy have been almostthe exclusive strategy for identifying the marketed compounds. However, the actual structuraland functional information about the molecular targets of the anticonvulsant drugsand the increasing knowledge of the molecular alterations that generate epileptic seizuresallow 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 anoverview of the computational approaches (docking-based virtual screening and moleculardynamics) to find anticonvulsant structures that interact with the voltage-gated ionchannels and the enzyme carbonic anhydrase. The second one includes the analysis of activecompounds synthesized to act simultaneously on different molecular targets by thecombination of pharmacophores of anticonvulsant drugs.Conclusion: Current knowledge of the architectures of anticonvulsant targets makes computationalsimulations attractive methods for the discovery and optimization of activecompounds. Combining the results achieved by virtual screening of different targetscould lead to multitarget compounds, as an alternative to the design of structures thatmerge scaffolds of known drugs