Sohrab Sayed Sartaj, Kamal Mohammad Amjad
Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 22254, Saudi Arabia.
Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 22254, Saudi Arabia.
Life (Basel). 2022 Oct 28;12(11):1729. doi: 10.3390/life12111729.
Breast cancer (BC) is one of the most frequent types of cancer that affect women. Human epidermal growth factor receptor-2 (HER2) is responsible for 20% of all BC cases. The use of anti-HER2 natural compounds in the cure of BC that is HER2-positive patients has resulted in significant increases in survival in both early and advanced stages. The findings of in-silico research support the use of ligands as possible HER2 inhibitors, and molecules with high free energy of binding may have considerable anti-BC action, making them candidates for future drug development. The inhibitory activity of selected ligands like ZINC43069427 and ZINC95918662 against HER2 was found to be -11.0 and -8.50 kcal/mol, respectively. The amino acid residues Leu726, Val734, Ala751, Lys753, Thr798, Gly804, Arg849, Leu852, Thr862, and Asp863 were found in common interaction as compared to the control compound Lapatinib. Molecular dynamics study calculations of these selected potent inhibitors were conducted and found to be stable over the 50 ns simulation time in terms of root mean square deviation (RMSD), root-mean square fluctuation (RMSF), radius of gyration (Rg), and solvent accessible surface area (SASA). In addition, there are several parameters such as absorption, distribution, metabolism, and excretion toxicity (ADMET), physicochemical, and drug-likeness that were checked and found in good range to be potential lead-like molecules. Several drug-likeness rules like Lipinski, Ghose, Veber, Egan, and Muegge were checked and found to be positive for these rules. Based on these calculations and different parameters, these top two selected natural compounds can be used as potential candidates for anti-HER2 for the management of BC.
乳腺癌（BC）是影响女性的最常见癌症类型之一。人表皮生长因子受体2（HER2）导致了所有BC病例中的20%。在治疗HER2阳性的BC患者时使用抗HER2天然化合物，已使早期和晚期患者的生存率显著提高。计算机模拟研究结果支持使用配体作为可能的HER2抑制剂，具有高结合自由能的分子可能具有相当大的抗BC作用，使其成为未来药物开发的候选物。发现所选配体如ZINC43069427和ZINC95918662对HER2的抑制活性分别为-11.0和-8.50千卡/摩尔。与对照化合物拉帕替尼相比，发现亮氨酸726、缬氨酸734、丙氨酸751、赖氨酸753、苏氨酸798、甘氨酸804、精氨酸849、亮氨酸852、苏氨酸862和天冬氨酸863这些氨基酸残基存在共同相互作用。对这些所选强效抑制剂进行了分子动力学研究计算，发现在50纳秒模拟时间内，就均方根偏差（RMSD）、均方根波动（RMSF）、回转半径（Rg）和溶剂可及表面积（SASA）而言是稳定的。此外，还检查了几个参数，如吸收、分布、代谢和排泄毒性（ADMET）、物理化学性质和类药性，发现处于良好范围内，使其成为潜在的类先导分子。检查了几个类药性规则，如Lipinski规则、Ghose规则、Veber规则、Egan规则和Muegge规则，发现这些规则对此均为阳性。基于这些计算和不同参数，这两种所选天然化合物可作为抗HER2治疗BC的潜在候选物。
