University of Pittsburgh School of Medicine, Department of Computational & Systems Biology, HillmanCancer Center Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213, USA.
Curr Top Med Chem. 2011;11(3):281-90. doi: 10.2174/156802611794072641.
PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a key mediator of apoptosis induced by a wide variety of stimuli. PUMA is particularly important in initiating radiation-induced apoptosis and damage in the gastrointestinal and hematopoietic systems. Unlike most BH3-only proteins, PUMA neutralizes all five known antiapoptotic Bcl-2 members though high affinity interactions with its BH3 domain to initiate mitochondria-dependent cell death. Using structural data on the conserved interactions of PUMA with Bcl-2-like proteins, we developed a pharmacophore model that mimics these interactions. In silico screening of the ZINC 8.0 database with this pharmacophore model yielded 142 compounds that could potentially disrupt these interactions. Thirteen structurally diverse compounds with favorable in silico ADME/Toxicity profiles have been retrieved from this set. Extensive testing of these compounds using cell-based and cell-free systems identified lead compounds that confer considerable protection against PUMA-dependent and radiation-induced apoptosis, and inhibit the interaction between PUMA and Bcl-xL.
PUMA（p53 上调的凋亡调节剂）是 Bcl-2 同源结构域 3（BH3）仅有的 Bcl-2 家族成员，也是多种刺激诱导凋亡的关键介质。PUMA 在启动辐射诱导的胃肠道和造血系统凋亡和损伤方面尤为重要。与大多数 BH3 仅有的蛋白不同，PUMA 通过其 BH3 结构域与所有五种已知的抗凋亡 Bcl-2 成员发生高亲和力相互作用，从而中和它们，以启动线粒体依赖性细胞死亡。利用关于 PUMA 与 Bcl-2 样蛋白的保守相互作用的结构数据，我们开发了一种模拟这些相互作用的药效团模型。使用该药效团模型对 ZINC 8.0 数据库进行计算机筛选，得到了 142 种可能破坏这些相互作用的潜在化合物。从该组中检索到 13 种具有良好的计算机药物代谢动力学/毒性特征的结构多样的化合物。对这些化合物进行广泛的基于细胞和无细胞的系统测试，确定了先导化合物，它们可显著防止 PUMA 依赖性和辐射诱导的凋亡，并抑制 PUMA 与 Bcl-xL 之间的相互作用。
