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Low-Barrier Hydrogen Bond Determines Target-Binding Affinity and Specificity of the Antitubercular Drug Bedaquiline
Abstract
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.
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Authors (4)
-
Antoni Marciniak
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- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
-
ACS Medicinal Chemistry Letters
no. 15,
pages 265 - 269,
ISSN: 1948-5875 - Language:
- English
- Publication year:
- 2024
- Bibliographic description:
- Słabońska J., Sappati S., Marciniak A., Czub J.: Low-Barrier Hydrogen Bond Determines Target-Binding Affinity and Specificity of the Antitubercular Drug Bedaquiline// ACS Medicinal Chemistry Letters -Vol. 15,iss. 2 (2024), s.265-269
- DOI:
- Digital Object Identifier (open in new tab) 10.1021/acsmedchemlett.3c00509
- Sources of funding:
-
- Free publication
- Verified by:
- Gdańsk University of Technology
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