Frontiers in chemistry · 2026
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.
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Alkhatip Ahmed A A M M, Raza Usama, Farag Ehab, Hamza Mohamed Khaled, Hosny Hisham, Sallam Amr, Farag Ahmed M G, Wagih Mohamed, Naguib Amr, Abdulmegid Ahmed Mostafa, Algameel Haytham, Bahr Mahmoud Hussein
Аннотация
INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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).
DISCUSSION: 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.
METHODS: 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.
RESULTS: 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).
DISCUSSION: 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.