氢键
基岩
化学
残留物(化学)
抗药性
药物靶点
立体化学
药品
组合化学
生物物理学
计算生物学
生物化学
生物
分子
药理学
结核分枝杆菌
医学
肺结核
遗传学
有机化学
病理
作者
Joanna Słabońska,Subrahmanyam Sappati,Antoni Marciniak,Jacek Czub
标识
DOI:10.1021/acsmedchemlett.3c00509
摘要
The role of short strong hydrogen bonds (SSHBs) in ligand-target binding remains largely unexplored, thereby hindering a potentially important avenue in rational drug design. Here we investigate the interaction between the antituberculosis drug bedaquiline (Bq) and the mycobacterial ATP synthase to unravel the role of a specific hydrogen bond to a conserved acidic residue in the target affinity and specificity. Our ab initio molecular dynamics simulations reveal that this bond belongs to the SSHB category and accounts for a substantial fraction of the target binding free energy. We also demonstrate that the presence of an extra acidic residue, i.e., aspartic acid at position 32 (D32), found exclusively in mycobacteria, cooperatively enhances the HB strength, ensuring specificity for the mycobacterial target. Consistently, we show that the removal of D32 markedly weakens the affinity, leading to Bq resistance associated with mutations of D32 to nonacidic residues. By designing simple Bq analogs, we then explore the possibility to overcome the resistance and potentially broaden the Bq antimicrobial spectrum by making the SSHB independent of the presence of the extra acidic residue.
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