A multiple-step screening protocol to identify norepinephrine and dopamine reuptake inhibitors for depression
Panpan Wang, Fengmei Yan, Jianghong Dong, Shengqiang Wang, Yu Shi, Mengdan Zhu, Yuting Zuo, Hui Ma, Ruirui Xue, Dingjie Zhai, Xiaoyu Song
Abstract
assays as a novel NDRI lead compound due to its strongest druggability and balancing activities. Encouragingly, 3719810 performed comparative activities on two targets, with Ki values of 7.32 μM for hNET and 5.23 μM for hDAT. To obtain candidates with additional activities and balance the activities of 2 targets, 5 analogs were optimized, and 2 novel scaffold compounds were successively designed. By assessment of molecular docking, molecular dynamics simulations, and binding energy calculations, 5 compounds were validated as NDRI candidates with high activities, and 4 of them performed acceptable balancing activities acting on hNET and hDAT. This work supplied promising novel NDRIs for treatment of depression with cognitive dysfunction or other related neurodegenerative disorders, and also provided a strategy for highly efficient and cost-effective identification of inhibitors for dual targets with homologous non-targets.