Structure-Based Virtual Screening Identifies Novobiocin, Montelukast, and Cinnarizine as TRPV1 Modulators with Anticonvulsant Activity In Vivo

The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel, known to be involved in the regulation of many important physiological and pathological processes. In the last few years, it has been proposed as a promising target to develop novel anticonvulsant compounds. However, thermoregulatory effects associated with the channel inhibition have hampered the path for TRPV1 antagonists to become marketed drugs. In this regard, we conducted a structure-based virtual screening campaign to find potential TRPV1 modulators among approved drugs, which are known to be safe and thermally neutral. To this end, different docking models were developed and validated by assessing their pose and score prediction powers. Novobiocin, montelukast, and cinnarizine were selected from the screening as promising candidates for experimental testing and all of them exhibited nanomolar inhibitory activity. Moreover, the in vivo profiles showed promising results in at least one of the three models of seizures tested.瞬时感受器电位香草酸受体1（TRPV1）是一类非选择性阳离子通道，已知参与诸多重要生理与病理过程的调控。近年来，该受体被视作开发新型抗惊厥化合物的极具潜力的靶点。然而，通道抑制所伴随的体温调节效应，却阻碍了TRPV1拮抗剂成为上市药物的研发路径。有鉴于此，本研究开展了基于结构的虚拟筛选工作，旨在已上市的安全且热中性药物中挖掘潜在的TRPV1调节剂。为此，研究团队构建了多种分子对接模型，并通过评估其构象与打分预测能力完成模型验证。本次筛选最终选出诺维霉素、孟鲁司特与桂利嗪作为实验验证候选化合物，三者均展现出纳摩尔级的抑制活性。此外，体内活性表征结果显示，在受试的三种癫痫模型中，至少一种模型上呈现出令人满意的活性表现。