Cheminformatics approach for identification of <i>N-HyMenatPimeMelly</i> as a novel potential ligand against RAS and renal chloride channel
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Some angiotensin receptor (AR) blockers interfere with the renal chloride channel (ClC-K), which plays an important role in urine concentration. Identifying ligands targeting this channel, whether activating or blocking, is highly desirable because it could open the way for interventions that modulate their activity. In this study, the Asinex (BioDesign) complete library was screened to identify a compound with favorable physicochemical and pharmacokinetic properties, which have both AR blocking and ClC‐Ka-modulating activities to present it as a novel potential oral candidate which could be useful for treatment of salt-sensitive hypertension without major ClC‐K affection. A compound, N-{[4-Hydroxy-1-(2-methyl-1,6-naphthyridin-4-yl)-4-piperidinyl]methyl}-N-methyl-L-lysinamide (<i>N-HyMenatPimeMelly)</i> (Chem Spider ID 68416221), was identified as a potent potential oral ligand of the renin-angiotensin system (RAS) and ClC-Ka with docking scores ranging from −10.978 to −7.324 with the four selected proteins (4YAY: AR type 1, 2PFI: Cytoplasmic domain of ClC-Ka, 6JOD: AR type 2 and 6M0J: Angiotensin-converting enzyme 2). The protein-ligand complex was used to perform molecular dynamics (MD) simulation for 100 ns. The QikProp and SwissADME tools’ results showed that the compound has ADME/T and drug-likeness properties, which are within the permissible ranges for 95% of known drugs. The density functional theory (DFT) analysis and MD simulation extended the study toward computational validation. Throughout the study, <i>N-HyMenatPimeMelly</i> has shown good interactions and stable performance in MD simulation and DFT analysis. The whole analysis has produced promising results, and <i>N-HyMenatPimeMelly</i> can be treated as a novel potential RAS and ClC-K oral ligand, however, experimental validation is needed before human use. Communicated by Ramaswamy H. Sarma
部分血管紧张素受体（angiotensin receptor, AR）拮抗剂可作用于在尿液浓缩过程中发挥重要作用的肾脏氯离子通道（renal chloride channel, ClC-K）。鉴定靶向该通道的配体（无论激动剂还是拮抗剂）极具价值，因为这将为调控其活性的干预手段开辟新路径。本研究对阿西内克斯（生物设计公司，Asinex (BioDesign)）全库进行筛选，以获得同时具备AR阻断与ClC-Ka调节活性、理化及药代动力学特性优良的化合物，将其作为新型潜在口服候选药物，有望用于治疗盐敏感性高血压且不会对ClC-K造成显著影响。研究最终鉴定出化合物N-{[4-羟基-1-(2-甲基-1,6-萘啶-4-基)-4-哌啶基]甲基}-N-甲基-L-赖氨酰胺（N-HyMenatPimeMelly）（Chem Spider编号：68416221），其作为肾素-血管紧张素系统（renin-angiotensin system, RAS）与ClC-Ka的强效潜在口服配体，针对4种筛选蛋白（4YAY：1型AR；2PFI：ClC-Ka胞质结构域；6JOD：2型AR；6M0J：血管紧张素转换酶2）的分子对接得分介于-10.978至-7.324之间。随后以该蛋白-配体复合物为对象开展100纳秒的分子动力学（molecular dynamics, MD）模拟。通过QikProp与SwissADME工具分析的结果显示，该化合物的ADME/T（吸收、分布、代谢、排泄/毒性）及成药性参数均处于95%已知药物的允许范围内。本研究进一步结合密度泛函理论（density functional theory, DFT）分析与MD模拟完成计算验证。在整个研究过程中，N-HyMenatPimeMelly均表现出良好的相互作用特性与稳定的模拟性能。各项分析均得到了极具前景的结果，N-HyMenatPimeMelly可被视为新型潜在的RAS与ClC-K口服配体，但在应用于人体前仍需开展实验验证。本文由Ramaswamy H. Sarma通讯。
