2018年以bcl2蛋白家族为靶点的抗肿瘤药物设计-文档资料.ppt
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1、Outline,Background Hallmarks of Cancer The Bcl-2 Protein Family Model of BH3 mimetic-induced apoptosis Structure basis for designing ligands Small molecule inhibitors Peptidomimetic approach mimic the a-helix of the BH3 peptides ABT-737, ABT-263 and their analogs pan-active inhibitor of Bcl-2 Select
2、ive Bcl-2 inhibitors selective BCL-xL inhibitor Selective Mcl-1 inhibitors,1,Cell,144(5): 646-674,Hallmarks of Cancer,2,Extrinsic and intrinsic pathways of apoptosis,Expert Opin. Ther. Patents (2012) ,22(1):37-55,3,The Bcl-2 Protein Family,The Bcl-2 Family Proteins with anti- or pro-apoptotic functi
3、on Characteristics: (Often) a C-terminal transmembrane domain. Bcl-2 homology (BH) domains. Bcl-2 proteins form homo- and heterodimers via their BH-domains,BH1, BH2: Predicted to form ion channels BH3: The ”suicide domain” regulates cell death BH4: Thought to confer anti-apoptotic activity.,(Chan &
4、Yu. (2004). Clin. Exp. Pharmacol. Physiol. 31: 119). Chipuk, J. E,Molecular Cell ,2010,37(3): 299-310,4,Elevated of Bcl-2 or Bcl-xL expression,Seminars in Oncology, 2004,30(Supplement 16): 133-142.,5,Model of BH3 mimetic-induced apoptosis,一、直接模型: 抑制剂代替促凋亡蛋白BAK/BAX,与抗凋亡蛋白Bcl-2/Bcl-xl结合,从而抑制后者,促进细胞凋亡
5、二、间接模型 抑制剂替代特定的激活因子BH3-only蛋白,与抗调亡蛋白如BCL-2/BCL-xL结合,游离出来的BH3-only蛋白,激活BAK/BAX。,Nature Reviews Drug Discovery 2008,7(12): 989-1000 Clinical Cancer Research 2009,15(4): 1126-1132. Oncogene ,2009,27(S1): S149-S157.,6,Structure basis for designing ligands,7,The molecular basis for heterodimer formation,
6、Heterodimerization between members of the Bcl-2 family of proteins is a key event in the regulation of apoptosis pro-apoptotic protein(Bak) adopts an amphipathic a- helix(BH3 domain) that interacts with anti-apoptotic proteins(Bcl-xl) through hydrophobic and electrostatic interactions in the hydroph
7、obic cleft.,8,抗凋亡蛋白(BCL-2)是通过其表面疏水凹槽与促凋亡类(BIM)的 BH3区域结合发生相互作用,调节细胞正常的生理凋亡。,BCL-2 family antagonists for cancer therapy. Nature Reviews Drug Discovery 2008,7(12): 989-1000,Overlay of BCL-XLABT-737 complex with BCL-xlLBIM BH3 complex,Bcl-2 and BIM BH3,9,Bcl-xL and Bak-BH3,Surface representation of the
8、 binding pocket of Bcl-xL bound to the Bak peptide,10,. “Structure of Bcl-xL-Bak Peptide Complex: Recognition Between Regulators of Apoptosis.“ Science 1997,275(5302): 983-986.,Bcl-xL-Bim BH3,Mcl-1Bim BH3,Bcl-xL/Bad,Protein Science ,2000, 9:25282534,11,5个疏水中心 (P1, P2, P3, P4和P5) 4个氢键供体 (D1, D2, D3和
9、D4) 2个氢键受体 (A1 and A2),Bcl-2活性部位分布图,在受体D1、D2、D3、A1位点出现比较频繁,与受体形成静电作用能提高亲和力与特异性 D4,A2位点出现频率较小,能量贡献不大,BMC,2007, 15(19): 6407-6417,Small molecule inhibitors,Peptidomimetic approach mimic the a-helix of the BH3 peptides ABT-737, ABT-263 and their analogs pan-active inhibitor of Bcl-2 Selective Bcl-2 inh
10、ibitors selective BCL-xL inhibitor Selective Mcl-1 inhibitors,13,Bak,Peptidomimetic approach mimic the a-helix of the BH3 peptides,JACS,2005,127(29): 10191-10196 JACS,2005,127(15): 5,463-5468,14,J Biol Chem. 2011 ,18; 286(11): 93829392,Organic Letters,2007, 9(19): 3733-3736.,Bim BH3 a-helix,J. Med.
11、Chem. 2012, 55, 1073510741,15,ABT-737, ABT-263 and their analogs,16,SAR by NMR与ABT-737系列的发现,SAR by NMR(由Shuker小组开发):通过NMR技术将合理性药物设计和非合理性药物设计(组合化学)巧妙地结合起来,产生了一种极为有效的发现药物靶分子高亲和性配体的方法。 步骤:1、筛选出一个和15N标记的靶蛋白结合的小分子 2、对第一个小分子类似物进行筛选, 通过结构与活性的关系进行优化。 3、用同样的方法得到与第二个位点结合的 第二个小分子,并对其筛选、优化。并用多维NMR技术测定 蛋白质和两个配体的
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