Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases

Bacterial histidine kinases (HKs)
are quintessential regulatory
enzymes found ubiquitously in bacteria. Apart from their regulatory
roles, they are also involved in the production of virulence factors
and conferring resistance to various antibiotics in pathogenic microbes.
We have previously reported compounds that inhibit multiple HKs by
targeting the conserved catalytic and ATP-binding (CA) domain. Herein,
we conduct a detailed structure–activity relationship assessment
of adenine-based inhibitors using biochemical and docking methods.
These studies have resulted in several observations. First, interaction
of an inhibitor’s amine group with the conserved active-site
Asp is essential for activity and likely dictates its orientation
in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold
is highly preferred for binding to conserved Gly:Asp:Asn residues.
Lastly, hydrophobic electron-withdrawing groups at several positions
in the adenine core enhance potency. The selectivity of these inhibitors
was tested against heat shock protein 90 (HSP90), which possesses
a similar ATP-binding fold. We found that groups that target the ATP-lid
portion of the catalytic domain, such as a six-membered ring, confer
selectivity for HKs.