Department of Physics, University of Alberta, Edmonton, AB, Canada.
J Mol Graph Model. 2010 Feb 26;28(6):555-68. doi: 10.1016/j.jmgm.2009.12.003. Epub 2009 Dec 14.
The p53 protein, a guardian of the genome, is inactivated by mutations or deletions in approximately half of human tumors. While in the rest of human tumors, p53 is expressed in wild-type form, yet it is inhibited by over-expression of its cellular regulators MDM2 and MDMX proteins. Although the p53-binding sites within the MDMX and MDM2 proteins are closely related, known MDM2 small-molecule inhibitors have been shown experimentally not to bind to its homolog, MDMX. As a result, the activity of these inhibitors including Nutlin3 is compromised in tumor cells over-expressing MDMX, preventing these compounds from fully activating the p53 protein. Here, we applied the relaxed complex scheme (RCS) to allow for the full receptor flexibility in screening for dual-inhibitors that can mutually antagonize the two p53-regulator proteins. First, we filtered the NCI diversity set, DrugBank compounds and a derivative library for MDM2-inhibitors against 28 dominant MDM2-conformations. Then, we screened the MDM2 top hits against the binding site of p53 within the MDMX target. Results described herein identify a set of compounds that have been computationally predicted to ultimately activate the p53 pathway in tumor cells retaining the wild-type protein.
p53 蛋白是基因组的守护者，大约有一半的人类肿瘤中其会因突变或缺失而失活。在其余的人类肿瘤中，p53 以野生型形式表达，但它会被其细胞调节因子 MDM2 和 MDMX 蛋白的过表达所抑制。虽然 MDMX 和 MDM2 蛋白中的 p53 结合位点密切相关，但实验表明，已知的 MDM2 小分子抑制剂不会与其同源物 MDMX 结合。因此，在过度表达 MDMX 的肿瘤细胞中，这些抑制剂（包括 Nutlin3）的活性受到损害，从而阻止这些化合物完全激活 p53 蛋白。在这里，我们应用松弛复合物方案（RCS）允许受体充分灵活，以筛选能够相互拮抗两种 p53 调节蛋白的双重抑制剂。首先，我们筛选了 NCI 多样性集合、DrugBank 化合物和针对 28 种主导 MDM2 构象的 MDM2 抑制剂衍生库。然后，我们筛选了 MDM2 的顶级命中，以针对 MDMX 靶标内的 p53 结合位点。本文所描述的结果确定了一组化合物，这些化合物经计算预测最终将激活保留野生型蛋白的肿瘤细胞中的 p53 途径。
