糖尿病治療薬アモルファス薬物の構造解明(Cracking the code of amorphous drugs for diabetes treatment)

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2025-05-14 スイス連邦工科大学ローザンヌ校(EPFL)

糖尿病治療薬アモルファス薬物の構造解明(Cracking the code of amorphous drugs for diabetes treatment)
A visualisation of the molecular jumble present in the amorphous GLP-1R agonist, as determined by NMR spectroscopy. Although it looks random at first sight, the structure allows one to identify the hydrogen-bonding interactions and preferred conformations that stabilise the amorphous form of the drug. Credit: Jacob Holmes (EPFL)

スイス連邦工科大学ローザンヌ校(EPFL)とアストラゼネカの研究チームは、非晶質(アモルファス)医薬品の原子レベル構造を3Dで初めて解明する手法を開発しました。GLP-1受容体作動薬候補にこの手法を適用し、糖尿病や肥満治療薬の経口投与実現に貢献する可能性があります。固体NMR、機械学習(ShiftML2)、分子動力学シミュレーションを組み合わせ、900万通りの分子環境を解析。水素結合が構造安定化に寄与し、特定のねじれ角を持つ化学構造が結晶化を抑制することを明らかにしました。

<関連情報>

グルカゴン様ペプチド-1受容体アゴニストの3次元原子レベル構造を解明 Three-Dimensional Atomic-Level Structure of an Amorphous Glucagon-Like Peptide-1 Receptor Agonist

Daria Torodii,Manuel Cordova,Jacob B. Holmes,Pinelopi Moutzouri,Tommaso Casalini,Sten O. Nilsson Lill,Arthur C. Pinon,Christopher S. Knee,Anna Svensk Ankarberg,Okky Dwichandra Putra,Staffan Schantz,and Lyndon Emsley
Journal of the American Chemical Society  Published: May 7, 2025
DOI:https://doi.org/10.1021/jacs.5c01925

Abstract

Amorphous formulations are increasingly used in the pharmaceutical industry due to their increased solubility, but their structural characterization at atomic-level resolution remains extremely challenging. Here, we characterize the complete atomic-level structure of an amorphous glucagon-like peptide-1 receptor (GLP-1R) agonist using chemical shift driven NMR crystallography. The structure is determined from measured chemical shift distributions for 17 of the 32 carbon atoms and 16 of the 31 hydrogen atoms in the molecule. The chemical shifts are able to provide a detailed picture of the atomic-level conformations and interactions, and we identify the structural motifs that play a major role in stabilization of the amorphous form. In particular, hydrogen bonding of the carboxylic acid proton is strongly promoted, although no carboxylic acid dimer is formed. Two orientations of the benzodioxole ring are promoted in the NMR structure, corresponding to a significant stabilization mechanism. Our observation that inclusion of water leads to stabilization of the carboxylic acid group might be used as a strategy in future formulations where hydrogen bonding between neighboring molecules may otherwise be hindered by sterics.

有機化学・薬学
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