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. 2018 Feb 27;8:3733. doi: 10.1038/s41598-018-21893-x

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© The Author(s) 2018

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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

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Modification of small molecule antagonists of the integrin α4β1. (A,B) Structure and activity of the small molecule integrin antagonists. Studies showing α4β1-expressing-K562 cell adhesion to plastic-immobilized vascular cell adhesion molecule-1 (VCAM-1). An average “Percent Adhesion” from at least 6 independent experiments is shown (average ± SEM). (C) Molecular Dynamics simulation of THI0565 binding into the integrin α4β1 ectodomain. THI0565 is anchored by the carboxylic acid coordination of the β1 MIDAS Mg⁺⁺ ion (green sphere, expanded 2x for visualization) and the 2-hydroxyethoxyphenyl group hydrophobic interactions with α4 residues PHE214 and TYR187. The pyridone hydroxyl appears readily available for modification (red square). (D,E) Modifications of THI0520 and THI0565 to generate targeting conjugates for liposome formulation. (F,G) Inhibitory activity (IC₅₀) of modified compounds as determined in α4β1-K562 cell adhesion assays to VCAM-1.