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. 2023 Dec 6;14:8064. doi: 10.1038/s41467-023-43718-w

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a 3D human KOR structure with small molecule agonist MP1104 was used as the starting template (PDB: 6B73). b Workflows for computational peptide–small molecule conjugate design: (1) Measurement of the pocket area (934 Å3) narrowed down the size of macrocycles to focus on 5- and 6-mer cyclic peptides. (2) Generation of small molecules with two additional amino acids, which were sampled and scored for optimal dimer sequence (select dipeptide modified small molecules: Gray: CVV-D-Phe-Thr; Yellow: CVV-D-Phe-Gln; Orange: CVV-D-Phe-Ser; CVV corresponds to N-cyclopropylmethyl-epoxy morphinan small molecule stub). (3) Generation of a comprehensive library of 5- and 6-mer thioether cyclized peptides clustered via torsion angle and hydrogen bond pattern. (4) Docked structure of thioether macrocyclized hexamers through coordinate-guided transformation of the backbone C-termini to the generated anchor N-termini. (5) Rotamer design to optimize the interface interactions of the backbones. (6) Design filtering based on shape complementarity and interface area as representative examples for interface metrics; dashed red line represents 90th percentile cut-off values.