Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, via del Liceo 1, 06123 Perugia, Italy.
J Chem Inf Model. 2010 Aug 23;50(8):1451-65. doi: 10.1021/ci100113p.
The design and optimization of small molecule inhibitors of the murine double minute clone 2-p53 (p53-MDM2) interaction has attracted a great deal of interest as a way to novel anticancer therapies. Herein we report 3D-QSAR studies of 41 small molecule inhibitors based on the use of molecular interaction fields and docking experiments as part of an approach to generating predictive models of MDM2 affinity and shedding further light on the structural elements of the ligand-target interaction. These studies have yielded predictive models explaining much of the variance of the 41 compound training set and satisfactorily predicting with 75% success an external test set of 36 compounds. Not surprisingly, and in full agreement with previous data, inspection of the 3D-QSAR coefficients reveals that the major driving force for potent inhibition is given by the hydrophobic interaction between the inhibitors and the p53 binding cleft of MDM2. More surprisingly, and challenging previous suggestions, the projection of the 3D-QSAR coefficients back onto the experimental structures of MDM2 provides an intriguing hypothesis concerning an active role played by the N-terminal region of MDM2 in ligand binding.
小分子抑制剂设计与优化作为一种新型抗癌疗法，针对鼠双微体 2-p53（p53-MDM2）相互作用引起了广泛关注。本文报道了基于分子相互作用场和对接实验的 41 种小分子抑制剂的 3D-QSAR 研究，作为生成 MDM2 亲和力预测模型的方法之一，并进一步阐明配体-靶相互作用的结构要素。这些研究产生了可以解释 41 个化合物训练集大部分方差的预测模型，并且可以成功地以 75%的成功率预测 36 个化合物的外部测试集。不出所料，与之前的数据完全一致，对 3D-QSAR 系数的分析表明，抑制剂与 MDM2 的 p53 结合裂隙之间的疏水相互作用是产生强效抑制的主要驱动力。更令人惊讶的是，并且对之前的建议提出了挑战，将 3D-QSAR 系数投影回 MDM2 的实验结构提供了一个有趣的假设，即 MDM2 的 N 端区域在配体结合中发挥积极作用。
