Structure-based molecular modeling of a novel S-Remiketamine scaffold and derived arylcyclohexanone analogues: NMDA receptor dynamics, MM-GBSA ranking, and CES1-Oriented structural compatibility.
Ahmed A A M M Alkhatip, Usama Raza, Ehab Farag, Mohamed Khaled Hamza, Hisham Hosny, Amr Sallam, Ahmed M G Farag, Mohamed Wagih, Amr Naguib, Ahmed Mostafa Abdulmegid, Haytham Algameel, Mahmoud Hussein Bahr
Frontiers in chemistry 2026 DOI: 10.3389/fchem.2026.1922077 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Computational modeling study Peer reviewed |
|---|---|
| Measures | Glide score, MM-GBSA |
| Topics | Esketamine Ketamine |
| Keywords | Mm-gbsa Nmda receptor S-remiketamine Carboxylesterase 1 Computer-aided drug design Molecular dynamics Molecular modeling |
| Key points | The authors report that R2 ranked highest in static NMDA receptor docking (Glide score -7.308 kcal/mol) and that R14 was the only evaluated compound whose CES1 MM-GBSA became more favorable from 0 to 100 ns (-83.91 to -99.44 kcal/mol). They propose R2 as the strongest static NMDA docking benchmark and R14 as the most internally consistent integrated computational candidate, while stating these results are hypothesis-generating and require experimental validation. |
Abstract
Short-acting ketamine-related scaffold design remains an important medicinal-chemistry problem, but computational studies require conservative interpretation until receptor, enzymatic, and pharmacokinetic validation is available. S-ketamine, S-Remiketamine, and R1-R20 analogues were assessed using ligand curation, NMDA receptor docking, cross-target docking, explicit-solvent molecular dynamics, MM-GBSA analysis, CES1-oriented geometric assessment, and predictive ADMET/metabolite-route analysis. Static NMDA docking ranked R2 highest (Glide score -7.308 kcal/mol), while S-Remiketamine showed a more favorable predicted NMDA score than S-ketamine (-6.448 vs. -5.981 kcal/mol). Within the dynamically evaluated subset, NMDA end-state MM-GBSA values were -41.53 kcal/mol for R2, -28.80 kcal/mol for R11, and -42.10 kcal/mol for R14. In CES1 modeling, R14 was the only evaluated compound whose MM-GBSA became more favorable from 0 to 100 ns (-83.91 to -99.44 kcal/mol). These results support R2 as the strongest static NMDA docking/NMDA-preference benchmark and R14 as the most internally consistent integrated computational candidate. The findings are hypothesis-generating and require synthesis and experimental validation.