Low-Barrier Hydrogen Bond Determines Target-Binding Affinity and Specificity of the Antitubercular Drug Bedaquiline.

ABSTRACT: 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 my

SUBMITTER: Slabonska J 

PROVIDER: S-EPMC10860170 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature