3D-QSAR, HQSAR, molecular docking, and new compound design study of 1,3,6-trisubstituted 1,4-diazepan-7-ones as human KLK7 inhibitors

Abstract

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.