当前位置: X-MOL 学术ACS Omega › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Small Molecules Targeting the Inactive Form of the Mnk1/2 Kinases
ACS Omega ( IF 4.1 ) Pub Date : 2017-11-14 00:00:00 , DOI: 10.1021/acsomega.7b01403
Srinivasaraghavan Kannan 1 , Mohan R. Pradhan 1 , Joseph Cherian 2 , Thomas L. Joseph 1 , Zhi Ying Poh 2 , Yang Hai Yan 2 , Ho Melvyn 2 , Liu Boping 2 , Hill Jeffrey 2 , Kassoum Nacro 2 , Chandra S. Verma 1, 3, 4
Affiliation  

Overexpression of the eukaryotic initiation factor 4E (eIF4E) is linked to a variety of cancers. Both mitogen-activated protein kinases-interacting kinases 1 and 2 (Mnk1/2) activate the oncogene eIF4E through posttranslational modification (phosphorylating it at the conserved Ser209). Inhibition of Mnk prevents eIF4E phosphorylation, making the Mnk–eIF4E axis a potential therapeutic target for oncology. Recently, the design and synthesis of a series of novel potent compounds inhibiting the Mnk1/2 kinases were carried out in-house. Here, we describe computational models of the interactions between Mnk1/2 kinases and these inhibitors. Molecular modeling combined with free energy calculations show that these compounds bind to the inactive forms of the kinases. All compounds adopt similar conformations in the catalytic sites of both kinases, stabilized by hydrogen bonds with the hinge regions and with the catalytic Lys78 (Mnk1) and Lys113 (Mnk2). These hydrogen bond interactions clearly play a critical role in determining the conformational stability and potency of the compounds. We also find that van der Waals interactions with an allosteric pocket are key to their binding and potency. Two distinct hydration sites that appear to further stabilize the ligand binding/interactions were observed. Critically, the inclusion of explicit water molecules in the calculations results in improving the agreement between calculated and experimental binding free energies.

中文翻译:

针对Mnk1 / 2激酶的非活性形式的小分子

真核起始因子4E(eIF4E)的过表达与多种癌症有关。丝裂素激活的蛋白激酶相互作用的激酶1和2(Mnk1 / 2)都通过翻译后修饰(在保守的Ser209处使其磷酸化)激活癌基因eIF4E。抑制Mnk可防止eIF4E磷酸化,使Mnk–eIF4E轴成为肿瘤学的潜在治疗靶标。最近,在室内进行了一系列抑制Mnk1 / 2激酶的新型有效化合物的设计和合成。在这里,我们描述了Mnk1 / 2激酶与这些抑制剂之间相互作用的计算模型。分子建模与自由能计算相结合表明,这些化合物与激酶的失活形式结合。所有化合物在两种激酶的催化位点均采用相似的构象,通过与铰链区以及催化的Lys78(Mnk1)和Lys113(Mnk2)的氢键稳定。这些氢键相互作用显然在确定化合物的构象稳定性和效力中起关键作用。我们还发现与变构口袋的范德华相互作用是它们结合和效力的关键。观察到似乎进一步稳定配体结合/相互作用的两个不同的水合位点。至关重要的是,在计算中包含明确的水分子会改善计算的和实验的结合自由能之间的一致性。这些氢键相互作用显然在确定化合物的构象稳定性和效力中起关键作用。我们还发现与变构口袋的范德华相互作用是它们结合和效力的关键。观察到似乎进一步稳定配体结合/相互作用的两个不同的水合位点。至关重要的是,在计算中包含明确的水分子会改善计算的和实验的结合自由能之间的一致性。这些氢键相互作用显然在确定化合物的构象稳定性和效力中起关键作用。我们还发现与变构口袋的范德华相互作用是它们结合和效力的关键。观察到似乎进一步稳定配体结合/相互作用的两个不同的水合位点。至关重要的是,在计算中包含明确的水分子会改善计算的和实验的结合自由能之间的一致性。
更新日期:2017-11-14
down
wechat
bug