Ameji Philip John, Shtaiwi Amneh, Adnan Rohana
School of Chemical Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia.
Department of Chemistry, Federal University Lokoja, P.M.B. 1154, Lokoja, Nigeria.
Toxicol Rep. 2025 Jan 25;14:101926. doi: 10.1016/j.toxrep.2025.101926. eCollection 2025 Jun.
The declining efficacies of existing drugs against estrogen receptor positive (ER+) breast cancer due to multidrug resistance, acute toxicities, and poor pharmacokinetic properties has necessitated the discovery of newer ones. In this study, colchicine analogues with proven activities against breast cancer cells were screened against estrogen receptor alpha (ERα) molecular docking simulations to identify some promising drug candidates. The identified ligands were further subjected to MM/GBSA calculations to ascertain their solvation-dependent Gibb's free energy of binding (∆G). Three most promising ligands (MPLs); 12, 16, and 21 with ∆G values of - 40.37, - 40.31, and - 40.26 kcal/mol, respectively, were identified. When compared with tamoxifen (standard drug) whose ∆G value is - 38.66 kcal/mol, the MPLs appear more potent. The kinetic stabilities of 12, 16, and 21 were confirmed by DFT (B3LYP/6-31G*) calculations and the time-dependent thermodynamic stabilities of their complexes with ERα were established by molecular dynamic simulations. In addition, the MPLs display positive pharmacokinetic and toxicity profiles and could be excellent sources of potent and non-toxic drug candidates against ER+ breast carcinoma.
由于多药耐药性、急性毒性和不良的药代动力学特性，现有药物对雌激素受体阳性（ER+）乳腺癌的疗效不断下降，因此有必要发现更新的药物。在本研究中，针对雌激素受体α（ERα）进行分子对接模拟，筛选出已证实对乳腺癌细胞有活性的秋水仙碱类似物，以确定一些有前景的候选药物。对鉴定出的配体进一步进行MM/GBSA计算，以确定其溶剂化依赖性结合吉布斯自由能（∆G）。确定了三种最有前景的配体（MPLs）；12、16和21，其∆G值分别为-40.37、-40.31和-40.26 kcal/mol。与∆G值为-38.66 kcal/mol的他莫昔芬（标准药物）相比，MPLs似乎更有效。通过DFT（B3LYP/6-31G*）计算证实了12、16和21的动力学稳定性，并通过分子动力学模拟确定了它们与ERα复合物的时间依赖性热力学稳定性。此外，MPLs显示出良好的药代动力学和毒性特征，可能是抗ER+乳腺癌的有效且无毒候选药物的优秀来源。
