Structure‐Binding Relationship of 2‐Amino‐1,8‐Naphthyridine Dimers: Role of Linkage Positions on DNA and RNA Recognition

TL;DR

This study shows how changing the connection positions of a molecule affects its ability to bind to DNA and RNA, influencing its structure and function for potential therapeutic applications.

Contribution

The study reveals how linkage positions in 2-amino-1,8-naphthyridine dimers affect their conformation and nucleic acid binding specificity.

Findings

ANP77 showed the strongest stabilization of cytosine-rich DNA motifs.

RNA binding patterns varied with sequence specificity, as shown by fluorescence quenching.

Hierarchical clustering linked molecular conformations to binding preferences.

Abstract

The study explores the synthesis, structural analysis, and binding properties of eight analogs of 2‐amino‐1,8‐naphthyridine dimers (ANPxys) targeting DNA and RNA. These dimers, derived from ANP77, are connected at varying positions to investigate how positional alterations influence molecular conformations and their interactions with nucleic acids. The primary focus lies on evaluating the effects of these structural variations on DNA and RNA binding through fluorescence quenching and thermal denaturation assays. Absorption and fluorescence measurements revealed distinct electronic states for ANPxys, with emission maxima between 389.5 and 398.5 nm. Conformational analysis indicated that most ANPxys adopt unstacked conformations in aqueous solutions, though some, like ANP47 and ANP67, showed higher probabilities of stacked conformations. Thermal denaturation studies demonstrated ANPxys bind and stabilize cytosine‐rich DNA motifs with varying affinities, with ANP77 showing the strongest effects. RNA binding studies targeting U/CC motifs across 256 sequences revealed unique fluorescence quenching patterns for each ANPxy, reflecting sequence specificity. Hierarchical clustering grouped ANPxys into parallel‐stacked and twisted‐stacked clusters, correlating their conformations with binding preferences. This work highlights the critical role of connection positions in determining ANPxy binding specificity and conformational behavior. The findings provide a basis for designing small molecules with tunable structures and enhanced RNA‐binding capabilities, paving the way for the development of RNA‐targeted therapeutics.

Altering the connecting positions of two 2‐amino‐1,8‐naphthyridine units modulates binding to distinct DNA and RNA motifs. This structural variation influences molecular interactions, affecting stacking tendencies and hydrogen bonding. The positional differences determine how these molecules recognize cytosine‐rich sequences, impacting their ability to stabilize nucleic acid structures and paving the way for designing RNA‐targeted small molecules.

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