Inhibition of protein interactions: co-crystalized protein-protein interfaces are nearly as good as holo proteins in rigid-body ligand docking.
Inhibition of protein interactions: co-crystalized protein-protein interfaces are nearly as good as holo proteins in rigid-body ligand docking.
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DOI：
10.1007/s10822-018-0124-z
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发表时间：
2018-07
影响因子：
3.5
通讯作者：
Vakser IA
中科院分区：
文献类型：
--
作者：
Belkin S;Kundrotas PJ;Vakser IA
调节蛋白质相互作用途径可能会治愈许多疾病。已知的蛋白质-蛋白质抑制剂与蛋白质-蛋白质界面上的大口袋结合。在没有已知抑制剂的蛋白质-蛋白质复合物中也检测到了如此大的口袋，使得此类复合物具有潜在的可成药性。抑制剂结合位点主要由形成蛋白质结合构象中最大口袋的侧链定义。低分辨率配体对接显示，蛋白质结合构象的成功率与配体结合构象的成功率接近，并且显着高于apo构象。与其他蛋白质结合后蛋白质界面上的构象变化导致配体在与该界面结合时使用口袋。这项概念验证研究表明，人们可以选择通过实验确定的目标共结晶蛋白质-蛋白质复合物的结构作为药物设计的起点，而不是使用计算口袋打开程序。
Modulating protein interaction pathways may lead to the cure of many diseases. Known protein-protein inhibitors bind to large pockets on the protein-protein interface. Such large pockets are detected also in the protein-protein complexes without known inhibitors, making such complexes potentially druggable. The inhibitor-binding site is primary defined by the side chains that form the largest pocket in the protein-bound conformation. Low-resolution ligand docking shows that the success rate for the protein-bound conformation is close to the one for the ligand-bound conformation, and significantly higher than for the apo conformation. The conformational change on the protein interface upon binding to the other protein results in a pocket employed by the ligand when it binds to that interface. This proof-of-concept study suggests that rather than using computational pocket-opening procedures, one can opt for an experimentally determined structure of the target co-crystallized protein-protein complex as a starting point for drug design.
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影响因子：
5.7
作者：
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通讯作者：
Nikiforovich, Gregory V.
影响因子：
7.3
作者：
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通讯作者：
Helms, Volkhard
影响因子：
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通讯作者：
Bushweller, John H.
影响因子：
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作者：
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影响因子：
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通讯作者：
Roche P