This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Drug discovery has traditionally followed the "rule of 5," which identifies chemical properties generally associated with good absorption of orally administered drugs, including a molecular weight below 500 daltons (Da). However, some pharmaceutical compounds fall outside these guidelines.
Known as beyond rule of 5 (bRo5) molecules, these compounds can have larger, more complex structures while still exhibiting strong therapeutic activity and favorable pharmacological properties. Their size and structural complexity, however, make it difficult to characterize them using conventional methods, particularly when very small quantities are available. Now, researchers led by doctoral student Taichi Baba from the Department of Chemistry, Institute of Science Tokyo (Science Tokyo), Japan, have developed a flexible metal–organic framework, APF-40 (APF = adaptable porous framework), that enables structural analysis of large bRo5 molecules from microgram-scale samples.
APF-40 acts as a crystalline sponge, trapping guest molecules within its porous structure and holding them in place, thereby enabling molecular structure determination by single-crystal X-ray diffraction analysis. The research team included former graduate student Yu Tagami; former assistant professor Yuki Wada, current director of TEKMOF Co. Ltd., Japan; specially appointed associate professor Pavel M.
Usov; and Professor Masaki Kawano, who also serves as chief scientific officer of TEKMOF Co. Ltd., from Science Tokyo, along with Associate Professor Arihiro Iwasaki from Chuo University in Japan. Their study was published in the Journal of the American Chemical Society on Aug. 19, 2026.
"We have successfully extended the crystalline sponge method to the structural analysis of molecules larger than 500 Da using only microgram-scale samples, overcoming a long-standing limitation of the technique," Baba said. The researchers synthesized APF-40 using a benzoate-substituted hexaazaphenalene ligand and Zn8 clusters, which form a doubly interpenetrated framework with channels about 1 nm wide. These include larger channels measuring 17.4 × 12.5 Å2, as well as smaller channels between the Zn8 clusters.
Water molecules and dimethylammonium ions inside the channels form hydrogen-bonding networks that provide additional sites for guest molecules to interact with the framework. These interactions help APF-40 hold guest molecules securely inside its channels. Using APF-40, the researchers successfully determined the structures of 12 pharmaceutical molecules, including eight bRo5 compounds with subtle differences in their chemical structures, such as methyl-to-ethyl, methoxy-to-hydroxy and alkane-to-alkene modifications.
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