# De Novo Generation-Based Design of Potential Computational Hits Targeting the GluN1-GluN2A Receptor

## TL;DR

This study designs new drug candidates targeting the GluN1-GluN2A receptor for treating CNS disorders like depression, showing better binding and inhibition than existing drugs.

## Contribution

The paper introduces three novel antagonists with stronger binding affinity than (S)-ketamine, designed using a de novo drug design approach.

## Key findings

- Three compounds showed ∆Gbinding values below −18.98 kcal/mol, indicating stronger binding than (S)-ketamine.
- MD simulations confirmed stable receptor binding and a mechanism similar to (S)-ketamine.
- Electrophysiological tests showed concentration-dependent inhibition of receptor currents by up to 41.76%.

## Abstract

Central nervous system (CNS) disorders such as depression severely impair human health. Targeted inhibition of the GluN1-GluN2A receptor is a promising therapeutic strategy, but current drugs often have adverse effects. To develop novel candidate drugs, this study utilized the (S)-ketamine and GluN1-GluN2A receptor complex as a structural template and conducted de novo drug design with the DrugFlow platform. An integrated strategy of molecular docking-based virtual screening combined with high-throughput binding free energy (∆Gbinding) calculations from large-scale molecular dynamics (MD) simulations identified three promising antagonists. The ∆Gbinding values of these compounds are all below −18.98 kcal/mol, indicating stronger binding affinity than (S)-ketamine, and they demonstrate promising drug-like properties and development potential. 200-ns MD simulations confirmed their stable receptor binding and mechanism consistent with (S)-ketamine. Electrophysiological recordings revealed that, at a concentration of 10 μM, Compounds A1, A2, and A3 produced concentration-dependent inhibition of GluN1-GluN2A receptor-mediated currents, with fractional inhibition values of 24.26%, 35.36%, and 41.76%, respectively. These findings demonstrate the compounds’ potential as CNS disorder therapeutics, requiring further experiments to validate efficacy and advance development for conditions like depression.