A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910
Diarylquinolines (DARQ's) are a new class of potent inhibitors of the ATPase of Mycobacterium tuberculosis and some other bacterial ATP synthases. We have created a homology model of a binding site for this class of compounds, which is located on the contact area of the a-subunit (gene atpB) and c-subunits (gene atpE) of Mycobacterium tuberculosis ATPase. The binding pocket that was identified from the analysis of the homology model is formed by 4 helices of three c-subunits and 2 helices of the a-subunit. The lead compound of the DARQ series, R207910, was docked into the pocket using our simulated annealing, multiple conformer, docking algorithm. Different stereoisomers were treated separately. The best docking pose for each stereoisomer was optimized by molecular dynamics simulation on the 5300 atoms of the binding region and ligand.
The interaction energies in the computed complexes enable us to rank
the different stereoisomers in order of interaction strength with
the ATPase binding pockets. We propose that the activity
of R207910 against Mycobacterium tuberculosis
is based on interference of the compound with the escapement geometry
of the proton transfer chain. Upon binding the compound mimicks the
conserved Arg-186 residue of the a-subunit and interacts in its place
with the conserved acidic residue Glu-61 of the c-subunit.
This mode of action is corroborated by the good agreement between
the computed interaction energies and the observed pattern of
stereo-specificity in the model of the binding region.
More details on this study
are available in our publications.
A model for human β-Secretase
Human β-Secretase model, color-coded by electrostatic potential, with peptide analog inhibitor colored by atom charge.