Abstract

The p53 gene is mutated in greater than 50% of several human cancers including bladder urothelial carcinoma, lung adenocarcinoma, colorectal carcinoma, and oral cancer. Mutations in the p53 gene occur predominantly in the DNA-binding domain causing loss of function and accumulation of dysfunctional p53 protein in tumors by hetero-oligomerization with the wild type p53. Thus an in silico approach for the rational design of potent, pharmacologically active small drug-like compounds targeting mutated p53 was undertaken. Molecular dynamics simulations of the wild type p53 monomer and p53 mutants R175H and R248Q were performed using Discovery Studio v3.5. Phase was used to generate pharmacophore models and the sitemap generated pocket was used to screen the Maybridge HitFinder^TM library using Schrodinger Suite. We identified ten compounds (Cmpd-1 to Cmpd-10) that showed preferential binding to p53 mutants, and their pharmacokinetic profiles complied with the ADMET rules. Cmpd-4 and Cmpd-8 demonstrated binding with mutated p53 at cysteine 124, similar to the mutant p53 reactivating compound APR-246 (PRIMA-1^Met) for functional restoration of the mutant p53. We propose the identified compounds as suitable drug candidates against mutated p53 protein, with the specific small drug-like molecules as either single drugs or in combination with lower doses of additional cytotoxic drugs, consequently reducing adverse side effects in patients.

Communicated by Ramaswamy H. Sarma

摘要

p53 基因在超过 50% 的几种人类癌症中发生突变，包括膀胱尿路上皮癌、肺腺癌、结肠直肠癌和口腔癌。p53 基因的突变主要发生在 DNA 结合结构域，通过与野生型 p53 的异源寡聚化，导致功能丧失和功能失调的 p53 蛋白在肿瘤中的积累。因此，采用计算机方法合理设计针对突变 p53 的有效的、药理活性的小药物样化合物。使用 Discovery Studio v3.5 进行野生型 p53 单体和 p53 突变体 R175H 和 R248Q 的分子动力学模拟。Phase 用于生成药效团模型，站点地图生成的口袋用于筛选 Maybridge HitFinder ^TM使用薛定谔套件的图书馆。我们鉴定了十种化合物（Cmpd-1 到 Cmpd-10），它们显示出优先结合 p53 突变体，并且它们的药代动力学特征符合 ADMET 规则。Cmpd-4 和 Cmpd-8 在半胱氨酸 124 处与突变的 p53 结合，类似于用于突变 p53 功能恢复的突变 p53 重新激活化合物 APR-246 (PRIMA-1 ^Met )。我们建议将鉴定出的化合物作为针对突变 p53 蛋白的合适候选药物，将特定的小药物样分子作为单一药物或与较低剂量的其他细胞毒性药物联合使用，从而减少患者的不良副作用。

由 Ramaswamy H. Sarma 传达