Bacterial Histidine Kinases (HKs) are an attractive target for the design of new antibiotics.[1,2] Nevertheless, the design of satisfactory HK inhibitors has been proven to be a challenge.[3] Drug selectivity depends on the conformation of a highly flexible loop that closes on top of the binding site, known as the �ATP-lid�.[4] Here we have studied the binding of radicicol and JH-II-126 to the histidine kinase PhoQ using computational techniques. All-atom molecular dynamics combined with metadynamics provide information about the flexibility of the ATP-lid and the loop-drug interactions. Furthermore, free energy calculations give insight into the binding mode and affinity of the inhibitor. The results obtained constitute a first step in developing more potent and selective drugs.[1] Curr. Op. Microbiol. (2010) 13:232-239.[2] Annu. Rev. Biochem. (2000) 69:183-215.[3] J. Med. Chem. (2011) 54:915-929.[4] (a) J. Mol. Biol. (2008) 379:82-93. (b) Assay and Drug Development Technologies (2011) 9(2):174-183.

Unraveling the binding of histidine kinase inhibitors by molecular dynamics simulations

244th National Meeting (2012)

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