PDF(Pubmed)
Abstract：
Breast cancer (BC) is still one of the major issues in world health, especially for women, which necessitates innovative therapeutic strategies. In this study, we investigated the efficacy of retinoic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which plays a crucial role in the biosynthesis and metabolism of oestrogen and thereby influences the progression of BC and, the main objective of this investigation is to identify the possible drug candidate against BC through computational drug design approach including PASS prediction, molecular docking, ADMET profiling, molecular dynamics simulations (MD) and density functional theory (DFT) calculations. The result has reported that total eight derivatives with high binding affinity and promising pharmacokinetic properties among 115 derivatives. In particular, ligands 04 and 07 exhibited a higher binding affinity with values of -9.9 kcal/mol and -9.1 kcal/mol, respectively, than the standard drug epirubicin hydrochloride, which had a binding affinity of -8.2 kcal/mol. The stability of the ligand-protein complexes was further confirmed by MD simulations over a 100-ns trajectory, which included assessments of hydrogen bonds, root mean square deviation (RMSD), root mean square Fluctuation (RMSF), dynamic cross-correlation matric (DCCM) and principal component analysis. The study emphasizes the need for experimental validation to confirm the therapeutic utility of these compounds. This study enhances the computational search for new BC drugs and establishes a solid foundation for subsequent experimental and clinical research.
摘要：
乳腺癌（BC）仍然是世界健康的主要问题之一，尤其是对女性来说,这就需要创新的治疗策略。在这项研究中,我们研究了维甲酸衍生物作为17β-羟基类固醇脱氢酶1型（17β-HSD1）抑制剂的功效，在雌激素的生物合成和代谢中起着至关重要的作用，从而影响BC的进展，这项调查的主要目的是通过计算药物设计方法，包括PASS预测，确定针对BC的可能候选药物。分子对接,ADMET分析，分子动力学模拟(MD)和密度泛函理论(DFT)计算。结果已经报道了115个衍生物中总共8个具有高结合亲和力和有希望的药代动力学性质。特别是,配体04和07表现出更高的结合亲和力，值为-9.9kcal/mol和-9.1kcal/mol，分别,比标准药物盐酸表柔比星，其具有-8.2kcal/mol的结合亲和力。通过MD模拟在100-ns的轨迹上进一步证实了配体-蛋白质复合物的稳定性，其中包括对氢键的评估，均方根偏差(RMSD)，均方根波动(RMSF)，动态互相关矩阵(DCCM)和主成分分析。该研究强调需要进行实验验证以确认这些化合物的治疗效用。这项研究增强了对新BC药物的计算搜索，并为后续的实验和临床研究奠定了坚实的基础。
