Masoodi Tariq A, Alhamdanz Adel H
College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
Bioinformation. 2010 Jun 15;5(1):11-5. doi: 10.6026/97320630005011.
Mutant form of H-Ras (Harvey-Ras) proteins are found in almost 10%-25% of human tumours. Mutational activation transforms it into an oncogenic form, which results in the loss of intrinsic GTPase function and therefore the protein is constitutively in the active, GTP-bound state and is continuously sending signals for cell growth and proliferation. In the present insilico study, the inhibitory effect of different flavonoid compounds on mutant H Ras protein p21 has been assessed. In addition, inhibitory effect of flavonoids is compared with 3 known anticancer drugs. Upon docking, it was found that flavonoids such as Naringenin, Daidzein, and Hesperetin showed highest affinity (most negative ΔG), while Rutin showed no affinity towards mutant H Ras. The 3 clinical anticancer agents (Erlotinib, Letrozole and Exemestane) showed binding energies in the range of -1.11 to -5.51 kcal/mol which is comparatively lower than the flavonoids indicating efficacy of flavonoids in the treatment of cancer with little or no cytotoxicity. Our study demonstrates that flavonoids (particularly Naringenin, Daidzein, and Hesperetin) are the effective drugs to inhibit function of mutant H-Ras P21 protein, which in turn arrests the process of cell growth and proliferation of the cancer cell.
在近10%-25%的人类肿瘤中发现了H-Ras（哈维-鼠肉瘤病毒癌基因同源物）蛋白的突变形式。突变激活将其转化为致癌形式，导致内在GTP酶功能丧失，因此该蛋白持续处于活性的、结合GTP的状态，并不断发送细胞生长和增殖信号。在本计算机模拟研究中，评估了不同黄酮类化合物对突变型H Ras蛋白p21的抑制作用。此外，将黄酮类化合物的抑制作用与3种已知抗癌药物进行了比较。对接后发现，柚皮素、大豆苷元和橙皮素等黄酮类化合物显示出最高亲和力（最负的ΔG），而芦丁对突变型H Ras没有亲和力。3种临床抗癌药物（厄洛替尼、来曲唑和依西美坦）的结合能在-1.11至-5.51 kcal/mol范围内，相对低于黄酮类化合物，表明黄酮类化合物在治疗癌症方面具有疗效，且细胞毒性很小或没有。我们的研究表明，黄酮类化合物（特别是柚皮素、大豆苷元和橙皮素）是抑制突变型H-Ras P21蛋白功能的有效药物，这反过来又会阻止癌细胞的细胞生长和增殖过程。
