AI Article Synopsis
- - NMDA receptor antagonists show potential in treating various central nervous system disorders, including major depressive disorder, and this study focuses on optimizing a specific biphenyl-based NMDA negative allosteric modulator (NAM).
- - The optimization process, guided by free energy calculations, resulted in a significant increase in activity, improving the compound's effectiveness by 100 times (IC = 50 nM) compared to an initial hit found through virtual screening.
- - Preliminary results indicate this optimized NAM has low affinity for the hERG ion channel, an earlier hurdle for similar compounds, and it exhibits a unique binding mode that differs from another related NMDA NAM called EVT-101.
Article Abstract
NMDA (-methyl-d-aspartate) receptor antagonists are promising tools for the treatment of a wide variety of central nervous system impairments including major depressive disorder. We present here the activity optimization process of a biphenyl-based NMDA negative allosteric modulator (NAM) guided by free energy calculations, which led to a 100 times activity improvement (IC = 50 nM) compared to a hit compound identified in virtual screening. Preliminary calculation results suggest a low affinity for the human ether-a-go-go-related gene ion channel (hERG), a high affinity for which was earlier one of the main obstacles for the development of first-generation NMDA-receptor negative allosteric modulators. The docking study and the molecular dynamics calculations suggest a completely different binding mode (ifenprodil-like) compared to another biaryl-based NMDA NAM EVT-101.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298482 | PMC |
| http://dx.doi.org/10.1039/d2md00001f | DOI Listing |
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