Dept. of Biotechnology, 100 ft. Ring Road, Banashankari 3(rd)stage, PES University, Bengaluru, 560085, India.
Dept. of Biotechnology, 100 ft. Ring Road, Banashankari 3(rd)stage, PES University, Bengaluru, 560085, India; Dept. of Physiology & Pharmacology, Faculty of Medicine, University of Calgary, Canada.
Comput Biol Chem. 2019 Jun;80:398-408. doi: 10.1016/j.compbiolchem.2019.05.005. Epub 2019 May 16.
Pharmacological intervention to reactivate p53 in human tumors holds great promise for cancer patients. A number of small molecules that reactivate p53 mutants that are either specific to certain mutation or more broadly on various mutants of p53 are discovered by rational design and screening methods. One of the most remarkable among small molecules for the rescue of specific mutant p53, Y220C is PhiKan083 (1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine) that have been demonstrated effective in advanced pre-clinical trials. Our attempt here is to identify additional targets of p53 mutants for rescue drugs and provide insight into the molecular level interactions of the drug with the mutant target. In this study PhiKan083 also known as PK083 is investigated, screened and validated on 28 different mutants of p53 using FlexX. Interaction of PhiKan08 with Y220C is found to be largely hydrophobic and a crucial single H-bond interaction with Asp228 in addition to few electrostatic interactions. Our study identified Y220S mutant as an additional target for PK083 as it shows a similar interaction pattern. Besides this, Docking and MD simulation studies, showed that Y220S binds to PK083 at higher efficiency as a result of improved steric and hydrophobic environment in the binding cavity in comparison with known mutant target, Y220C. Further, we point out that structure guided optimization of PhiKan08 can lead to an improved drug that can interact favourably with yet another mutant, Y220 N. In addition, this study revealed that Y220H and other mutants including native p53 does not provide any favourable interaction with PhiKan08 which is in accord with the experimental findings. These findings can facilitate the selection of patients for clinical studies and cancer survival analysis.
药理学干预以重新激活人类肿瘤中的 p53 对癌症患者具有巨大的希望。通过合理的设计和筛选方法，发现了许多能够重新激活特定突变或广泛的 p53 各种突变体的 p53 突变体的小分子。在拯救特定突变 p53 的小分子中，最引人注目的是 Y220C 的 PhiKan083（1-(9-乙基-9H-咔唑-3-基）-N-甲基甲胺），它已在先进的临床前试验中证明有效。我们在这里的尝试是确定挽救药物的 p53 突变体的其他靶点，并深入了解药物与突变靶标的分子水平相互作用。在这项研究中，还研究了 PhiKan083，也称为 PK083，使用 FlexX 在 28 种不同的 p53 突变体上进行筛选和验证。发现 PhiKan08 与 Y220C 的相互作用主要是疏水的，除了少数静电相互作用外，还与 Asp228 形成关键的单个氢键相互作用。我们的研究确定 Y220S 突变体是 PK083 的另一个靶标，因为它显示出相似的相互作用模式。除此之外，对接和 MD 模拟研究表明，与已知的突变靶标 Y220C 相比，Y220S 在结合腔中具有改善的空间和疏水环境，因此以更高的效率与 PK083 结合。此外，我们指出，PhiKan08 的基于结构的优化可以导致能够与另一个突变体 Y220N 有利相互作用的改进药物。此外，这项研究表明，Y220H 和包括天然 p53 在内的其他突变体与 PhiKan08 没有提供任何有利的相互作用，这与实验结果一致。这些发现可以促进患者的临床研究和癌症生存分析的选择。
