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<p>C–H···O hydrogen bonds are regarded as weak and overlooked in structure-based drug design. Here, we demonstrate through quantum-chemical calculations that N(sp<sup>2</sup>)⁺–C(sp<sup>2</sup>)–H···O hydrogen bonds involving pyridinium ions exhibit strong and directional interactions with carbonyl oxygen atoms. Density-functional-theory (DFT) and natural-bond-orbital (NBO) analyses indicated that cationization increases the positive charge on adjacent sp<sup>2</sup> C–H protons, thereby enhancing their proton-donating ability. Fragment-based symmetry-adapted-perturbation-theory (F-SAPT) analyses revealed that these interactions remain significant even when the pyridine nitrogen is partially positively charged via interaction with another hydrogen-bond donor. Geometric criteria were established from a theoretical study and applied to a survey of protein–ligand complexes in the Protein Data Bank, and 55 protein kinase–inhibitor complexes exhibiting N(sp<sup>2</sup>)⁺–C(sp<sup>2</sup>)–H···O hydrogen bonds were identified. These findings indicate that N(sp<sup>2</sup>)⁺–C(sp<sup>2</sup>)–H···O hydrogen bonds are recurrent in protein–ligand complexes and provide a novel strategy for enhancing binding affinity in drug design.</p>

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Theoretical study on N(sp2)+–C(sp2)–H···O hydrogen bonds in the context of drug discovery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Miyuka Suzuki,
  • Yasunobu Yamashita,
  • Yuri Takada,
  • Yukihiro Itoh,
  • Takayoshi Suzuki

摘要

C–H···O hydrogen bonds are regarded as weak and overlooked in structure-based drug design. Here, we demonstrate through quantum-chemical calculations that N(sp2)⁺–C(sp2)–H···O hydrogen bonds involving pyridinium ions exhibit strong and directional interactions with carbonyl oxygen atoms. Density-functional-theory (DFT) and natural-bond-orbital (NBO) analyses indicated that cationization increases the positive charge on adjacent sp2 C–H protons, thereby enhancing their proton-donating ability. Fragment-based symmetry-adapted-perturbation-theory (F-SAPT) analyses revealed that these interactions remain significant even when the pyridine nitrogen is partially positively charged via interaction with another hydrogen-bond donor. Geometric criteria were established from a theoretical study and applied to a survey of protein–ligand complexes in the Protein Data Bank, and 55 protein kinase–inhibitor complexes exhibiting N(sp2)⁺–C(sp2)–H···O hydrogen bonds were identified. These findings indicate that N(sp2)⁺–C(sp2)–H···O hydrogen bonds are recurrent in protein–ligand complexes and provide a novel strategy for enhancing binding affinity in drug design.