Kondo Jiro

Small molecules that target RNA are emerging as a powerful therapeutic modality, although deriving structure–activity relationships (SARs) remains a major challenge. Here, we present AI ‐augmented I terative S creening of L ibraries A gainst R NA targets (AISLAR), a machine learning‐driven strategy that accelerates the discovery of SAR‐tractable RNA binders and enables rational analog design. We screened diverse, drug‐like chemical libraries against two RNA motifs derived from human p53 mRNA and applied AISLAR within the open‐source KNIME platform. The application of AISLAR yielded chemotypes suitable for SAR development. Biophysical assays confirmed direct binding of representative compounds to one RNA motif. Guided by early SAR trends, we developed a pharmacophore hypothesis and designed an analog that retained binding with lower predicted cardiac channel liability. Docking simulations using the crystal structure of the RNA motif revealed a plausible binding mode for the validated hit compound. While further validation across diverse RNA targets and compound libraries will be required, these results demonstrate how AISLAR can be used as a workflow linking RNA‐targeted small molecule screening with rational analog design.

Amiloride possesses a characteristic chemical scaffold capable of recognizing uracil (U) through three complementary hydrogen bonds; however, its binding selectivity toward naturally occurring RNA structural motifs has remained uncharacterized. In...

By modifying specific positions of 5′-CC G CGCG C GCCGCGAA-3′, we gained insight into crystal packing interactions of a 960-nm-emissive DNA-stabilized silver nanocluster.

Gold-mediated base pairing in nucleic acids has remained poorly understood, despite structural analogies with mercury and silver ions known to coordinate selectively to mismatched base pairs. Here, the crystal structures of a CAu(I)C base pair and a CGAu(I)C base triple formed with natural nucleobases are reported. Although solution-phase thermodynamic analysis of Au(I) coordination is technically unfeasible, structural evidence supports its selective insertion into the base mismatches. In contrast, duplexes incorporating 2-thiocytosine form square-planar complexes with Au(III), and melting temperature analysis shows significant thermal stabilization. The distinct coordination geometries of Au(I) and Au(III) arise from differences in oxidation state and preferred coordination numbers, with Au(I) favoring linear two-coordinate structures and Au(III) forming square-planar complexes stabilized by thiocarbonyl donors. These findings establish a structure-guided strategy for oxidation-state-selective metal coordination in nucleic acids, paving the way for the design of metal-responsive DNA architectures with tunable properties.