Computational
Design and Discovery of Nanomolar Inhibitors
of IκB Kinase β
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Abstract
IκB
kinase β (IKKβ) is a useful target for the
discovery of new medicines for cancer and inflammatory diseases. In
this study, we aimed to identify new classes of potent IKKβ
inhibitors based on structure-based virtual screening, <i>de
novo</i> design, and chemical synthesis. To increase the probability
of finding actual inhibitors, we improved the scoring function for
the estimation of the IKKβ-inhibitor binding affinity by introducing
proper solvation free energy and conformational destabilization energy
terms for putative inhibitors. Using this modified scoring function,
we have been able to identify 15 submicromolar-level IKKβ inhibitors
that possess the phenyl-(4-phenyl-pyrimidin-2-yl)-amine moiety as
the molecular core. Decomposition analysis of the calculated binding
free energies showed that a high biochemical potency could be achieved
by lowering the desolvation cost and the conformational destabilization
for the inhibitor required for binding to IKKβ as well as by
strengthening the interactions in the ATP-binding site. The formation
of two hydrogen bonds with backbone amide groups of Cys99 in the hinge
region was found to be necessary for tight binding of the inhibitors
in the ATP-binding site. From molecular dynamics simulations of IKKβ-inhibitor
complexes, we also found that complete dynamic stability of the bidentate
hydrogen bond with Cys99 was required for low nanomolar-level inhibitory
activity. This implies that the scoring function for virtual screening
and <i>de novo</i> design would be further optimized by
introducing an additional energy term to measure the dynamic stability
of the key interactions in enzyme–inhibitor complexes