Cryo-EM structure-based selection of computed ligand poses enables design of MTA-synergic PRMT5 inhibitors of better potency.
Cryo-EM structure-based selection of computed ligand poses enables design of MTA-synergic PRMT5 inhibitors of better potency.
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DOI：
10.1038/s42003-022-03991-9
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发表时间：
2022-10-03
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
2.5-4.0 äCryo-EM结构用于基于结构的药物设计的预测潜力尚未很好地实现。在这里，我们表明，3.1PRMT5的 ä结构适合于选择化学缓蚀剂及其类似物的计算姿势以增强效力。PRMT5是多种肿瘤类型的致癌靶点，有许多抑制剂与MTA几乎没有协同作用，MTA是一种在MTAP−/−细胞中积累的辅因子类似物。为了实现甲氨蝶呤的协同抑制，来自虚拟筛选的药效团导致了特定的抑制剂(11-2 F)。11-2 F/MTA结合的人PRMT5/MEP50复合体及其载脂蛋白形式的冷冻-EM结构表明，催化口袋中的11-2 F使辅因子结合口袋移开了~2.0 ä，有助于正协同作用。计算分析预测11-2 F在PRMT中的亚型特异性。对结合口袋中的配体进行了结构分析，以比较11-2 F及其重新设计的类似物的姿势，并确定了三个预测具有显著更好效力的新类似物。其中一种化合物经合成后，对PrMT5的抑制效率是11-2 F的~4倍，具有很强的MTA协同作用。这些数据表明，采用近原子分辨低温电磁结构和计算分析配体姿态用于小分子疗法是可行的。冷冻-EM MAP导向的药物设计和配基姿势的计算比较产生了一种PRMT5抑制剂或衍生物，它们是MTA协同作用的，并显示出增强的效力。
Projected potential of 2.5–4.0 Å cryo-EM structures for structure-based drug design is not well realized yet. Here we show that a 3.1 Å structure of PRMT5 is suitable for selecting computed poses of a chemical inhibitor and its analogs for enhanced potency. PRMT5, an oncogenic target for various cancer types, has many inhibitors manifesting little cooperativity with MTA, a co-factor analog accumulated in MTAP−/− cells. To achieve MTA-synergic inhibition, a pharmacophore from virtual screen leads to a specific inhibitor (11-2 F). Cryo-EM structures of 11-2 F / MTA-bound human PRMT5/MEP50 complex and its apo form resolved at 3.1 and 3.2 Å respectively show that 11-2 F in the catalytic pocket shifts the cofactor-binding pocket away by ~2.0 Å, contributing to positive cooperativity. Computational analysis predicts subtype specificity of 11-2 F among PRMTs. Structural analysis of ligands in the binding pockets is performed to compare poses of 11-2 F and its redesigned analogs and identifies three new analogs predicted to have significantly better potency. One of them, after synthesis, is ~4 fold more efficient in inhibiting PRMT5 catalysis than 11-2 F, with strong MTA-synergy. These data suggest the feasibility of employing near-atomic resolution cryo-EM structures and computational analysis of ligand poses for small molecule therapeutics. Cryo-EM map-guided drug design and computational comparison of ligand poses yield a PRMT5 inhibitor or derivatives that are MTA-synergic and show enhanced potency.
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DOI：
10.1042/bj20120768
发表时间：
2012-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Gu Z;Gao S;Zhang F;Wang Z;Ma W;Davis RE;Wang Z
通讯作者：
Wang Z
影响因子：
5.3
作者：
Dacwag, Caroline S.;Ohkawa, Yasuyuki;Imbalzano, Anthony N.
通讯作者：
Imbalzano, Anthony N.
影响因子：
3
作者：
Fuhrmann, Jan;Rurainski, Alexander;Neumann, Dirk
通讯作者：
Neumann, Dirk
影响因子：
8
作者：
Deng X;Shao G;Zhang HT;Li C;Zhang D;Cheng L;Elzey BD;Pili R;Ratliff TL;Huang J;Hu CD
通讯作者：
Hu CD
影响因子：
48
作者：
DiMaio, Frank;Song, Yifan;Li, Xueming;Brunner, Matthias J.;Xu, Chunfu;Conticello, Vincent;Egelman, Edward;Marlovits, Thomas C.;Cheng, Yifan;Baker, David
通讯作者：
Baker, David