Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening
Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening
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DOI：
10.1021/jm800151n
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发表时间：
2008-09-25
影响因子：
7.3
通讯作者：
Cruciani, Gabriele
中科院分区：
文献类型：
--
作者：
Carosati, Emanuele;Budriesi, Roberta;Cruciani, Gabriele
为了努力发现阻断L型钙通道（LTCCs）的新化学型，基于配体的虚拟筛选被应用，特别关注地尔硫卓结合位点。大约50,000种市售化合物作为筛选数据库。通过预测的药代动力学性质和结构要求进行筛选，将初始数据库减少到少数几种化合物，计算了它们与两种模板分子（地尔硫卓和4 - 氯 - N - 环丙基 - N -（4 - 哌啶基）苯磺酰胺，先前筛选实验中最有趣的命中化合物）的相似性。对18种化合物，在体外研究了其变力和变时活性以及对豚鼠的血管舒张作用，并且对最有希望的化合物，进行了对地尔硫卓位点的结合研究。该过程产生了几个命中化合物，证实了计算机模拟技术对于发现新化学型是有用的。特别是，N - [2 -（二甲基氨基）乙基] - 3 - 羟基 - 2 - 萘酰胺、N,N - 二甲基 - N' -（2 - 吡啶 - 3 - 基喹啉 - 4 - 基）乙烷 - 1,2 - 二胺、2 - [（4 - 氯苯基）（吡啶 - 2 - 基）甲氧基]N,N - 二甲基乙胺（卡比沙明）和7 - [2 -（二乙氨基）乙氧基] - 2H - 色烯 - 2 - 酮显示出有趣的活性以及与苯并硫氮杂卓位点的结合。
With the effort to discover new chemotypes blocking L-type calcium channels (LTCCs), ligand-based virtual screening was applied with a specific interest toward the diltiazem binding site. Roughly 50000 commercially available compounds served as a database for screening. The filtering through predicted pharmacokinetic properties and structural requirements reduced the initial database to a few compounds for which the similarity was calculated toward two template molecules, diltiazem and 4-chloro-N-cyclopropyl-N-(4-piperidinyl) ben zene-sulfonamide, the most interesting hit of a previous screening experiment. For 18 compounds, inotropic and chronotropic activity as well as the vasorelaxant effect on guinea pig were studied "in vitro", and for the most promising, binding studies to the diltiazem site were carried out. The procedure yielded several hits, confirming in silico techniques to be useful for finding new chemotypes. In particular, N-[2-(dimethylamino)ethyl]-3-hydroxy-2-naphthamide, N,N-dimethyl-N'-(2-pyridin-3-ylquinolin-4-yl)ethane-1,2-diamine, 2-[(4-chlorophenyl)(pyridin-2-yl)methoxy]N,N-dimethylethanamine (carbinoxamine), and 7-[2-(diethylamino)ethoxy]-2H-chromen-2-one revealed interesting activity and binding to the benzothiazepine site.