化学
钾通道
类风湿性关节炎
选择性
体内
药理学
立体化学
电压门控钾通道
结构-活动关系
离体
计算生物学
组合化学
体外
生物化学
内科学
医学
钾
遗传学
催化作用
生物
有机化学
作者
Louise Antonia Hendrickx,Vladimir Dobričić,Žan Toplak,Steve Peigneur,Lucija Peterlin Mašič,Tihomir Tomašić,Jan Tytgat
标识
DOI:10.1016/j.bioorg.2020.103746
摘要
The voltage-gated potassium channel Kv1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which Kv1.3 inhibitors arise as promising candidates. In this study, five compounds were selected based on a 3D similarity searching methodology and subsequently screened ex vivo on the Kv1.3 channel. The screening resulted in two compounds inhibiting the Kv1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for Kv1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the Kv1.3 channel and three Kv1.3 mutants, designed to resemble the pore region of Kv1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the Kv1.3 channel, resulting in a 20-fold higher potency for TVS-12.
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