The role of short strong hydrogen bonds (SSHB) in ligand-target binding remains largely unexplored, thereby hin- dering a potentially important avenue in the rational drug de- sign. Here, we investigate the interaction between bedaquiline (Bq), a potent anti-tuberculosis drug, 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 substan- tial fraction of the target binding energy. We also demonstrate that the presence of an extra acidic residue (D32), found exclu- sively in mycobacteria, cooperatively enhances the HB strength ensuring the specificity for the mycobacterial target. Consis- tently, we show that the removal of D32 markedly weakens the affinity, leading to Bq resistance associated with mutations of D32 to non-acidic residues. By designing simple Bq analogs, we then explore the possibility to overcome the resistance and po- tentially broaden the Bq antimicrobial spectrum by making the SSHB independent on the presence of the extra acidic residue.
Authors
Additional information
- DOI
- Digital Object Identifier link open in new tab 10.1021/acsmedchemlett.3c00509
- Category
- Publikacja w czasopiśmie
- Type
- artykuły w czasopismach
- Language
- angielski
- Publication year
- 2024
