Al Khzem Abdulaziz H, Alturki Mansour S, Almuzaini Ohood K, Wali Saad M, Almaghrabi Mohammed, Aldawsari Mohammed F, Abduljabbar Maram H, Alnemari Reem M, Almalki Atiah H, Rants'o Thankhoe A
Department of Pharmaceutical Chemistry, College of Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah 24342, Saudi Arabia.
Pharmaceuticals (Basel). 2025 Apr 30;18(5):662. doi: 10.3390/ph18050662.
Breast cancer, the most prevalent cancer among women globally, develops primarily in the breast's ducts or lobules. Drug resistance is a significant challenge in treating advanced cases, contributing to over 685,000 breast cancer-related deaths annually, and identifying novel compounds that inhibit key proteins is crucial for developing effective therapies. In this study, five transferase proteins with PDB IDs were selected due to their involvement in breast cancer: 1A52, 3PP0, 4EJN, 4I23, and 7R9V. Multitargeted docking studies were conducted using three different docking strategies and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) to calculate the binding affinities against the ZINC Natural compound library. Isoetin (ZINC000006523948), found mainly in Isoetaceae, was identified, and the results were compared with the Food and Drug Administration (FDA)-approved drug Tucatinib. In addition, molecular interaction fingerprints and pharmacokinetic profiling were evaluated. We also performed 5 ns WaterMap simulations to identify hydration sites and interactions, followed by 100 ns molecular dynamics (MD) simulations and MM/GBSA to assess the stability of the Isoetin-protein complexes. The docking results indicated that Isoetin demonstrated superior binding and docking scores ranging from -9.901 to -13.903 kcal/mol compared to Tucatinib, which showed values between -4.875 and -10.948 kcal/mol, suggesting Isoetin's potential efficacy as a therapeutic agent for breast cancer. Interaction fingerprints revealed significant interactions between Isoetin and key residues, including 28LEU, 12MET, 9PHE, 7ASP, 6ASN, and 6THR. The pharmacokinetics and DFT analysis of Isoetin supported its potential as a viable drug candidate. Furthermore, the 5 ns WaterMap simulations identified various hydration sites, and the 100 ns MD simulations showed that the Isoetin-protein complexes exhibited minimal deviations and fluctuations, indicating better stability than Tucatinib, and MM/GBSA confirmed Isoetin's superior binding stability. Isoetin, a natural compound identified through in silico screening, demonstrates significant promise as a potential therapeutic agent for breast cancer as it outperforms the FDA-approved drug Tucatinib, the respective native and FDA-approved drug. However, experimental validation is necessary before considering Isoetin for clinical use.
乳腺癌是全球女性中最常见的癌症，主要发生在乳腺导管或小叶中。耐药性是治疗晚期乳腺癌的重大挑战，每年导致超过68.5万人死于乳腺癌相关疾病，因此鉴定能够抑制关键蛋白的新型化合物对于开发有效的治疗方法至关重要。在本研究中，由于其与乳腺癌相关，选择了5种具有蛋白质数据银行（PDB）ID的转移酶蛋白：1A52、3PP0、4EJN、4I23和7R9V。使用三种不同的对接策略以及分子力学/广义玻恩表面积法（MM/GBSA）进行多靶点对接研究，以计算与锌天然化合物库的结合亲和力。鉴定出主要存在于水韭科植物中的异荭草素（ZINC000006523948），并将结果与美国食品药品监督管理局（FDA）批准的药物图卡替尼进行比较。此外，还评估了分子相互作用指纹图谱和药代动力学特征。我们还进行了5纳秒的水图模拟以识别水化位点和相互作用，随后进行100纳秒的分子动力学（MD）模拟和MM/GBSA以评估异荭草素 - 蛋白质复合物的稳定性。对接结果表明，与图卡替尼相比，异荭草素表现出更高的结合力和对接分数，范围为 -9.901至 -13.903千卡/摩尔，而图卡替尼的值在 -4.875至 -10.948千卡/摩尔之间，这表明异荭草素作为乳腺癌治疗药物具有潜在疗效。相互作用指纹图谱揭示了异荭草素与关键残基之间的显著相互作用，包括28位亮氨酸、12位甲硫氨酸、9位苯丙氨酸、7位天冬氨酸、6位天冬酰胺和6位苏氨酸。异荭草素的药代动力学和密度泛函理论（DFT）分析支持其作为一种可行的候选药物的潜力。此外，5纳秒的水图模拟确定了各种水化位点，100纳秒的MD模拟表明异荭草素 - 蛋白质复合物表现出最小的偏差和波动，表明其稳定性优于图卡替尼，并且MM/GBSA证实了异荭草素具有更高的结合稳定性。异荭草素是通过计算机筛选鉴定出的一种天然化合物，作为一种潜在的乳腺癌治疗药物显示出巨大的前景，因为它优于FDA批准的药物图卡替尼，即各自的天然药物和FDA批准的药物。然而，在考虑将异荭草素用于临床之前，需要进行实验验证。
