Omar Sara Ibrahim, Tuszynski Jack
Department of Oncology, University of Alberta, Edmonton, AB, Canada, T6G 1Z2.
Department of Physics, University of Alberta, Edmonton, AB, Canada, T6G 1Z2.
Chem Biol Drug Des. 2015 Aug;86(2):163-72. doi: 10.1111/cbdd.12480. Epub 2014 Dec 11.
The guardian of the genome, p53, is the most mutated protein found in all cancer cells. Restoration of wild-type activity to mutant p53 offers promise to eradicate cancer cells using novel pharmacological agents. Several molecules have already been found to activate mutant p53. While the exact mechanism of action of these compounds has not been fully understood, a transiently open pocket has been identified in some mutants. In our study, we docked twelve known activators to p53 into the open pocket to further understand their mechanism of action and rank the best binders. In addition, we predicted the absorption, distribution, metabolism, excretion and toxicity properties of these compounds to assess their pharmaceutical usefulness. Our studies showed that alkylating ligands do not all bind at the same position, probably due to their varying sizes. In addition, we found that non-alkylating ligands are capable of binding at the same pocket and directly interacting with Cys124. The comparison of the different ligands demonstrates that stictic acid has a great potential as a p53 activator in terms of less adverse effects although it has poorer pharmacokinetic properties.
基因组守护者p53是在所有癌细胞中发现的突变最多的蛋白质。恢复突变型p53的野生型活性有望使用新型药物根除癌细胞。已经发现几种分子可激活突变型p53。虽然这些化合物的确切作用机制尚未完全了解，但在一些突变体中已鉴定出一个瞬时开放的口袋。在我们的研究中，我们将12种已知的p53激活剂对接至该开放口袋中，以进一步了解它们的作用机制并对最佳结合剂进行排名。此外，我们预测了这些化合物的吸收、分布、代谢、排泄和毒性特性，以评估它们的药用价值。我们的研究表明，烷基化配体并非都结合在同一位置，这可能是由于它们大小不同。此外，我们发现非烷基化配体能够结合在同一口袋中并直接与Cys124相互作用。不同配体的比较表明，尽管stictic酸的药代动力学性质较差，但就不良反应较少而言，它作为p53激活剂具有很大潜力。
