用于发现新型抗惊厥化合物的基于计算和合成目标的方法

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.

Cite this article as:

Computational and Synthetic Target-based Approaches to the Discovery of Novel Anticonvulsant Compounds, Current Medicinal Chemistry 2021; 28 (33) . https://dx.doi.org/10.2174/0929867328666210506161234