Depression treatment
Can docking find new NMDA blockers for Alzheimer’s?
Open access · cc by · source: Europe PMC
A pharmacophore-docking-MD pipeline screened ZINC against GluN2B NMDA receptors and nominated six compounds with better predicted solvation binding than ifenprodil—still untested in cells or people.
Study at a glance
- Design
- Computational / modelling — Pharmacophore validation (20 known NMDA inhibitors + 380 DUDE decoys), ZINC virtual screen, Glide docking, MD/solvation free energy vs ifenprodil
- N
- N=6 · Six ZINC leads after 38,105 pharmacophore hits; pharmacophore test set 20 actives + 380 inactives
- Population
- In silico GluN2B/NMDAR ligands from ZINC and PDB ifenprodil-bound complexes; no new wet-lab or patient dosing
- Outcome
- Predicted binding (GlideScore, solvation free energy, ADMET) of six candidate Gly/NMDA antagonists versus ifenprodil
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Key findings
Six ZINC molecules (including ZINC13729211 and ZINC07430424) showed high predicted affinity, hydrogen bonding, stability, and better solvation-based affinity than ifenprodil with acceptable ADMET; authors propose them as Gly/NMDA antagonist starting points.
Methodology
Built a pharmacophore from known NMDAR inhibitors, validated it on 20 actives plus 380 DUDE decoys, filtered ZINC (38,105 hits), docked to ifenprodil-bound NMDAR with Glide, then ranked ADMET and solvation free energies.
Limitations
No enzyme, cell, animal, or Alzheimer-patient data; docking and MM-PBSA cannot prove clinical NMDA blockade or safety.
How this study connects
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