Abstract
BACKGROUND: (-)-Balanol is an ATP-mimicking inhibitor that non-selectively targets protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA). While PKA constantly shows tumor promoting activities, PKC isozymes can ambiguously be tumor promoters or suppressors. In particular, PKCε is frequently implicated in tumorigenesis and a potential target for anticancer drugs. We recently reported that the C5(S)-fluorinated balanol analogue (balanoid 1c) had improved binding affinity and selectivity for PKCε but not to the other novel PKC isozymes, which share a highly similar ATP site. The underlying basis for this fluorine-based selectivity is not entirely comprehended and needs to be investigated further for the development of ATP mimic inhibitors specific for PKCε. RESULTS: Using molecular dynamics (MD) simulations assisted by homology modelling and sequence analysis, we have studied the fluorine-based selectivity in the highly similar ATP sites of novel PKC (nPKC) isozymes. The study suggests that every nPKC isozyme has different dynamics behaviour in both apo and 1c-bound forms. Interestingly, the apo form of PKCε, where 1c binds strongly, shows the highest degree of flexibility which dramatically decreases after binding 1c. CONCLUSIONS: For the first time to the best of our knowledge, we found that the origin of 1c selectivity for PKCε comes from the unique dynamics feature of each PKC isozyme. Fluorine conformational control in 1c can synergize with and lock down the dynamics of PKCε, which optimize binding interactions with the ATP site residues of the enzyme, particularly the invariant Lys437. This finding has implications for further rational design of balanol-based PKCε inhibitors for cancer drug development.