A multiple-step screening protocol to identify norepinephrine and dopamine reuptake inhibitors for depression

Area of Science:

• Neuroscience and Pharmacology
• Drug Discovery and Development

Background:

• Depression significantly impacts global health, causing cognitive dysfunction and economic burden.
• Existing Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs) show limitations in efficacy and side effect profiles.
• There is an urgent need for novel NDRIs that improve cognitive function and minimize side effects.

Purpose of the Study:

• To selectively identify novel NDRI candidates targeting human norepinephrine transporter (hNET) and human dopamine transporter (hDAT).
• To discover antidepressants that treat depression and improve cognitive function without interfering with cognitive processes.
• To develop a comprehensive strategy for efficient dual-target inhibitor identification.

Main Methods:

• Utilized Support Vector Machine (SVM) models to screen compounds against hNET, hDAT, and non-target human serotonin transporter (hSERT).
• Integrated ADMET prediction, molecular docking, in vitro binding assays, molecular dynamics simulations, and binding energy calculations.
• Optimized lead compounds and designed novel scaffolds for improved activity and target balance.

Main Results:

• Identified 6522 compounds non-inhibitory to hSERT, followed by ADMET and docking to select potent hNET/hDAT binders.
• Compound 3719810 emerged as a lead NDRI with Ki values of 7.32 μM (hNET) and 5.23 μM (hDAT).
• Validated 5 compounds as NDRI candidates, with 4 demonstrating balanced activity on hNET and hDAT.

Conclusions:

• Successfully identified promising novel NDRI candidates for treating depression with cognitive dysfunction.
• The developed strategy offers a highly efficient and cost-effective method for discovering dual-target inhibitors.
• These findings support the development of new antidepressants for depression and related neurodegenerative disorders.