Molecular dynamics study of small molecule inhibitors of the Bcl-2 family
Molecular dynamics study of small molecule inhibitors of the Bcl-2 family
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DOI：
10.1002/prot.23083
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发表时间：
2011-09-01
影响因子：
2.9
通讯作者：
Purisima, Enrico O.
中科院分区：
文献类型：
--
作者：
Acoca, Stephane;Cui, Qizhi;Purisima, Enrico O.
我们对Bcl-2家族蛋白抑制剂ABT-737和obatoclax进行了对接和分子动力学模拟。我们模拟了ABT-737与Bcl-x(L)、Bcl-2和Mcl-1的结合模式，并研究了它们的动力学行为。我们发现ABT-737的氯苯末端的结合在所有三种蛋白质中都是相当稳定的。然而，与Bcl-x(L)或Bcl-2相比，苯哌嗪连接体组在Mcl-1中的流动性显著增强。p4结合位点上的s -苯基在Bcl-x(L)和Bcl-2中锚定良好，但在Mcl-1中更具流动性，尽管在Mcl-1中苯基环本身平均靠近p4结合位点。这种更大的迁移可能是由于Mcl-1上p3和p4结合位点的更大开放。计算的结合自由能与ABT-737对Mcl-1较弱的结合亲和力相一致。预测Obatoclax在Mcl-1的p1和p2结合位点结合，在Mcl-1缠绕的分子动力学模拟中，Obatoclax的结合模式相当稳定。模拟的结合模式表明，obatoclax能够抑制所有三种蛋白质，因为它仅利用p1和p2结合位点，这是一个相当狭窄的槽，在所有三种蛋白质中，与p4结合位点不同，p4结合位点在Mcl-1中要宽得多。
We carried out docking and molecular dynamics simulations on ABT-737 and obatoclax, which are inhibitors of the Bcl-2 family of proteins. We modeled the binding mode of ABT-737 with Bcl-x(L), Bcl-2, and Mcl-1 and examined their dynamical behavior. We found that the binding of the chlorobiphenyl end of ABT-737 was quite stable across all three proteins. However, the phenylpiperazine linker group was dramatically more mobile in Mcl-1 compared to either Bcl-x(L) or Bcl-2. The S-phenyl group at the p4 binding site was well-anchored in Bcl-x(L) and Bcl-2 but was somewhat more mobile in Mcl-1 although the phenyl ring itself on average stayed close to the p4 binding site in Mcl-1. This greater mobility is likely due to the greater openness of the p3 and p4 binding sites on Mcl-1. The calculated binding free energies were consistent with the much weaker binding affinity of ABT-737 for Mcl-1. Obatoclax was predicted to bind at the p1 and p2 binding sites of Mcl-1 and the binding mode was quite stable during the molecular dynamics simulation with Mcl-1 wrapping around the molecule. The modeled binding mode suggests that obatoclax is able to inhibit all three proteins because it makes use of the p1 and p2 binding sites alone, which is a fairly narrow groove in all three proteins unlike the p4 binding site, which is much broader in Mcl-1.