Azme Eva, Hasan Md Mahmudul, Ali Md Liakot, Alam Rashedul, Hoque Neamul, Noushin Fabiha, Kabir Mohammed Fazlul, Islam Ashraful, Nipun Tanzina Sharmin, Hossen S M Moazzem, Chung Hea-Jong
Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh.
Department of Biotechnology, Harrisburg University of Science and Technology, Harrisburg, PA, United States.
Front Chem. 2025 Apr 16;13:1527008. doi: 10.3389/fchem.2025.1527008. eCollection 2025.
Breast cancer (BC) remains a leading cause of cancer-related mortality in women. The oncoprotein MDM2 negatively regulates the tumor suppressor p53, and its overexpression in BC promotes tumor progression and resistance to therapy. Targeting the MDM2-p53 interaction represents a promising therapeutic approach. However, many existing MDM2 inhibitors suffer from poor pharmacokinetics and off-target toxicity, necessitating the discovery of novel, more selective alternatives. This study aims to identify natural terpenoid compounds with potent MDM2 inhibitory potential through computational approaches.
A library of 398 natural terpenoids was sourced from the NPACT database and filtered based on Lipinski's Rule of Five. A two-stage docking strategy was applied: 1) rigid protein-flexible ligand docking to screen for high-affinity binders, followed by 2) ensemble docking using multiple MDM2 conformations derived from molecular dynamics (MD) simulations. The top candidates were further evaluated for their pharmacokinetic and toxicity profiles using ADMET analysis. Finally, 150 ns MD simulations and binding free energy (MM-PBSA) calculations were performed to assess the stability and strength of protein-ligand interactions.
Three terpenoid compounds, olean-12-en-3-beta-ol, cabralealactone, and 27-deoxyactein demonstrated strong binding affinities toward MDM2 in ensemble docking studies. ADMET analysis confirmed their favorable pharmacokinetic properties. Further MD simulations indicated that these compounds formed highly stable complexes with MDM2. Notably, 27-deoxyactein exhibited the lowest binding free energy (-154.514 kJ/mol), outperforming the reference inhibitor Nutlin-3a (-133.531 kJ/mol), suggesting superior binding stability and interaction strength.
Our findings highlight 27-deoxyactein as a promising MDM2 inhibitor with strong binding affinity, stability, and a favorable pharmacokinetic profile. This study provides a computational foundation for further experimental validation, supporting the potential of terpenoid-based MDM2 inhibitors in BC therapy.
乳腺癌（BC）仍然是女性癌症相关死亡的主要原因。癌蛋白MDM2负向调节肿瘤抑制因子p53，其在乳腺癌中的过表达促进肿瘤进展和对治疗的抗性。靶向MDM2-p53相互作用是一种有前景的治疗方法。然而，许多现有的MDM2抑制剂存在药代动力学不佳和脱靶毒性的问题，因此需要发现新型、更具选择性的替代物。本研究旨在通过计算方法鉴定具有强大MDM2抑制潜力的天然萜类化合物。
从NPACT数据库获取398种天然萜类化合物的文库，并根据Lipinski的五规则进行筛选。应用两阶段对接策略：1）刚性蛋白-柔性配体对接以筛选高亲和力结合物，随后2）使用从分子动力学（MD）模拟获得的多种MDM2构象进行整体对接。使用ADMET分析对顶级候选物的药代动力学和毒性特征进行进一步评估。最后，进行150纳秒的MD模拟和结合自由能（MM-PBSA）计算，以评估蛋白质-配体相互作用的稳定性和强度。
在整体对接研究中，三种萜类化合物，齐墩果-12-烯-3-β-醇、卡布拉内酯和27-脱氧放线菌素对MDM2表现出强烈的结合亲和力。ADMET分析证实了它们良好的药代动力学性质。进一步的MD模拟表明，这些化合物与MDM2形成了高度稳定的复合物。值得注意的是，27-脱氧放线菌素表现出最低的结合自由能（-154.514 kJ/mol），优于参考抑制剂Nutlin-3a（-133.531 kJ/mol），表明其具有卓越的结合稳定性和相互作用强度。
我们的研究结果突出了27-脱氧放线菌素作为一种有前景的MDM2抑制剂，具有强大的结合亲和力、稳定性和良好的药代动力学特征。本研究为进一步的实验验证提供了计算基础，支持基于萜类的MDM2抑制剂在乳腺癌治疗中的潜力。
