{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:15:27Z","timestamp":1788419727361,"version":"build-2803163510"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fchem.2026.1922077","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:41:16Z","timestamp":1788417676000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["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"],"prefix":"10.3389","volume":"14","author":[{"given":"Ahmed A. A. M. 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