posted on 2024-01-08, 12:06authored byJoanna Słabońska, Subrahmanyam Sappati, Antoni Marciniak, Jacek Czub
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.