Department of Molecular Sciences, Macquarie University , Sydney, NSW 2109, Australia.
J Chem Inf Model. 2018 Feb 26;58(2):511-519. doi: 10.1021/acs.jcim.7b00504. Epub 2018 Jan 27.
(-)-Balanol is an adenosine triphosphate mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with limited selectivity. While PKA is known as a tumor promoter, PKC isozymes can be tumor promoters or suppressors. In particular, PKCε is frequently involved in tumorigenesis and a potential target for anticancer drugs. We recently reported that stereospecific fluorination of balanol yielded a balanoid with enhanced selectivity for PKCε over other PKC isozymes and PKA, although the global fluorine effect behind the selectivity enhancement is not fully understood. Interestingly, in contrast to PKA, PKCε is more sensitive to this fluorine effect. Here we investigate the global fluorine effect on the different binding responses of PKCε and PKA to balanoids using molecular dynamics (MD) simulations. For the first time to the best of our knowledge, we found that a structurally equivalent residue in each kinase, Thr184 in PKA and Ala549 in PKCε, is essential for the different binding responses. Furthermore, the study revealed that the invariant Lys, Lys73 in PKA and Lys437 in PKCε, already known to have a crucial role in the catalytic activity of kinases, serves as the main anchor for balanol binding. Overall, while Thr184 in PKA attenuates the effect of fluorination, Ala549 permits remote response of PKCε to fluorine substitution, with implications for rational design of future balanol-based PKCε inhibitors.
(-)-Balanol 是一种三磷酸腺苷类似物，可抑制蛋白激酶 C（PKC）同工酶和 cAMP 依赖性蛋白激酶（PKA），但选择性有限。虽然 PKA 被认为是肿瘤促进剂，但 PKC 同工酶可以是肿瘤促进剂或抑制剂。特别是，PKCε 经常参与肿瘤发生，是抗癌药物的潜在靶点。我们最近报道称，balanol 的立体特异性氟化生成了一种具有增强对 PKCε 选择性的 balanoid，而对其他 PKC 同工酶和 PKA 的选择性较低，尽管这种选择性增强背后的整体氟效应尚未完全理解。有趣的是，与 PKA 相反，PKCε 对这种氟效应更为敏感。在这里，我们使用分子动力学（MD）模拟研究了氟对 PKCε 和 PKA 与 balanoids 不同结合反应的整体氟效应。据我们所知，这是首次发现，每种激酶中结构上等效的残基，PKA 中的 Thr184 和 PKCε 中的 Ala549，对于不同的结合反应是必不可少的。此外，该研究表明，PKA 中不变的赖氨酸 Lys73 和 PKCε 中的赖氨酸 Lys437，已知在激酶的催化活性中起关键作用，作为 balanol 结合的主要锚点。总的来说，虽然 PKA 中的 Thr184 减弱了氟化的影响，但 PKCε 中的 Ala549 允许对氟取代的远程响应，这对基于未来 balanol 的 PKCε 抑制剂的合理设计具有重要意义。
