Molecular Docking of Selective Hypocretin (orexin) receptor 2 Agonists: Achieving Binding Energies Exceeding –14.2 kcal/mol via Soluble and Synthetically Accessible Supramolecular Scaffolds. Yaroslav G. Zaitsev ORCID: 0000-0002-0069-2997 Date: 21.02.2026 DOI: https://doi.org/10.5281/zenodo.18725152 E-mail: nabrosovnabrosov@gmail.com Abstract The Type II Orexin Receptor(OX2R) presents significant structural challenges that limit the development and availability of highly selective agonists. In this study, we leveraged intramolecular supramolecular interactions between core subunits to engineer a series of ligands capable of optimized volumetric filling of the receptor cavity. This was achieved through a dynamic supramolecular 'resonance sandwich' framework. These scaffolds incorporate critical orexin pharmacophores, ranging from aldehyde, carboxyl, and tetrazole groups extending deep into the pocket toward S3216.52, as well as T2315.46, N3246.55, H3507.39and T1112.61. Across the entire spectrum of designed molecules, from low-molecular-weight entities to larger complexes, a unified design principle prevails: the elimination of redundant steric centers, streamlined synthesis from accessible precursors, minimal conformational hinges, and a pre-defined resonant geometry. This methodology has yielded dozens of unique compounds exhibiting exceptional affinity and selectivity. The discovery of potent water- and lipid-soluble agonists, including simple derivatives of caffeic acid, underscores the potential of this approach. The orexin receptor (OX2R) belongs to a large family of GPCR receptors, which includes catecholamine receptors. The evolutionary ancestor of this extensive group was likely less selective and interacted with both small molecules and peptides, which likely allows for more effective use of catecholamine and aromatic profiles with increased volume. Thus, we achieved high affinity and agonistic binding without the use of direct peptide mimetics. Keywords: Hypocretin (Orexin) Receptor 2 (OX2R), GPCR Agonism, Selective Ligand Design, O43614 (UniProt), Molecular Docking, Supramolecular Scaffolds, Intramolecular Resonance, Dynamic Resonance Sandwich, Volumetric Cavity Filling, Pre-defined Geometry, Synthetic Accessibility, Aqueous Solubility, Caffeic Acid Derivatives, Non-chiral Agonists (Steric Center Elimination), Amphiphilic Ligands. Hyper Pharma