Title:Computational and Synthetic Target-based Approaches to the Discovery of Novel Anticonvulsant Compounds
Volume: 28
Issue: 33
关键词:
抗惊厥药物、癫痫、电压门控离子通道、碳酸酐酶、对接、虚拟筛选、多靶点药物、混合分子。
摘要:
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.
