The skin is an important barrier against environmental factors. Foregoing studies has shown that human KLK7 is a protease which promoted epidermal shedding, affected the epidermal barrier and increased the risk of atopic dermatitis. In this study, the structure and activity relationship of 40 human KLK7 inhibitors was explored by three-dimensional quantitative structure–activity relationship (3D-QSAR) and hologram quantitative structure–activity relationship (HQSAR). 3D-QSAR including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis fields (CoMSIA), and Topomer comparative molecular field analysis (Topomer CoMFA). From the data we got, the 3D-QSAR models (CoMFA with q² = 0.755, r² = 0.994; CoMSIA with q² = 0.602, r² = 0.980; Topomer CoMFA with q² = 0.644, r² = 0.929) and the HQSAR model (q² = 0.717, r² = 0.950) had a good predictability. Molecular docking was used to reveal the binding mode between the inhibitors and KLK7 protein further. 3D-QSAR, HQSAR, and molecular docking results also provided guidance for discovering new human KLK7 inhibitors. Finally, 13 new compounds were designed as potential human KLK7 inhibitors, and the predicted activity values showed an effective inhibition on human KLK7.

中文翻译：

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3D-QSAR，HQSAR，分子对接和1,3,6-三取代的1,4-二氮杂-7-酮类化合物作为人KLK7抑制剂的新化合物设计研究

皮肤是抵抗环境因素的重要屏障。先前的研究表明，人KLK7是一种蛋白酶，可促进表皮脱落，影响表皮屏障并增加特应性皮炎的风险。在这项研究中，通过三维定量结构-活性关系（3D-QSAR）和全息图定量结构-活性关系（HQSAR）探索了40种人KLK7抑制剂的结构和活性关系。3D-QSAR包括比较分子场分析（CoMFA），比较分子相似性指数分析场（CoMSIA）和拓扑异构体比较分子场分析（Topomer CoMFA）。从我们得到的数据来看，3D-QSAR模型（​​CoMFA的q ²  = 0.755，r ²  = 0.994； CoMSIA的q ² =q ²  = 0.602，r ²  = 0.980；q ²  = 0.644，r ²  = 0.929的拓扑CoMFA和HQSAR模型（q ²  = 0.717，r ²  = 0.950）具有良好的可预测性。分子对接用于进一步揭示抑制剂与KLK7蛋白之间的结合模式。3D-QSAR，HQSAR和分子对接结果也为发现新的人类KLK7抑制剂提供了指导。最后，设计了13种新化合物作为潜在的人KLK7抑制剂，预测的活性值显示出对人KLK7的有效抑制作用。