Supramolecular docking structure determination of alkyl-bearing molecules

Yitao Wu, Le Shi, Lei Xu, Jiale Ying, Xiaohe Miao, Bin Hua (), Zhijie Chen (), Jonathan L. Sessler () and Feihe Huang ()
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Yitao Wu: Zhejiang University
Le Shi: Zhejiang University
Lei Xu: Nanjing University
Jiale Ying: Zhejiang University
Xiaohe Miao: and Westlake Institute for Advanced Study
Bin Hua: Zhejiang University
Zhijie Chen: Zhejiang University
Jonathan L. Sessler: The University of Texas at Austin
Feihe Huang: Zhejiang University

Nature, 2025, vol. 640, issue 8059, 676-682

Abstract: Abstract Numerous natural products and drugs contain flexible alkyl chains. The resulting conformational motion can create challenges in obtaining single crystals and thus determining their molecular structures by single-crystal X-ray diffraction (SCXRD)1–11. Here we demonstrate that by using pillar[5]arene-incorporated metal–organic frameworks (MOFs) and taking advantage of pillar[5]arene−alkyl chain host−guest recognition12–15, it is possible to reduce this motion and bring order to alkyl-chain-containing molecules as the result of docking within accessible pillar[5]arene units present in an overall MOF. This has allowed the single-crystal structures of 48 alkyl-chain-containing molecules, including 6 natural products, 2 approved drugs and 18 custom-made compounds collected from 16 research groups, to be determined using standard SCXRD instrumentation. The structures of alkyl-chain-containing molecules derived from crude reaction products can also be determined directly by SCXRD analyses without further purification. The simplicity, high efficiency and apparent generality of the present pillar[5]arene-incorporated MOF-based supramolecular docking approach suggest that it could emerge as a new tool for the analyses of natural products and drugs that might not be amenable to traditional SCXRD-based structure determination.

Date: 2025
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DOI: 10.1038/s41586-025-08833-2

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