Farrokhnia Maryam, Mahnam Karim
The Persian Gulf Marine-Medicine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr ,Iran.
Biology Department, Faculty of Sciences, Shahrekord University, Shahrekord, Iran.
Iran J Pharm Res. 2017 Winter;16(1):173-186.
Zoanthamine-type alkaloids display a wide spectrum of biological effects. This study aimed to examine the inhibitory effects of norzoanthamine and its ten homologues of zoanthamine class on human fibroblast collagenase by modeling a three-dimensional structure of the ligands at collagenase using energy minimization, docking, molecular dynamics simulation and MM-PB/GBSA binding free energy calculations. The results showed that zoanthamide, zooxathellamine and enol-iminium form of norzoanthamine, with lower binding free energies than other compounds, are potent inhibitors of collagenase. However, the enol-iminium form of norzoanthamine showed a more inhibitory activity against collagenase than its keto form. This suggests that it can be used for treatment of many diseases such as osteoporosis, autoimmune diseases, and cancer. Zinc-binding residues such as His 118, His 122 and His 128 for hydrogen bonds and Leu 81, Tyr 110, Val 115, Leu 126, Pro 138, Ser 139 for hydrophobic interactions should be considered for designing an inhibitor for collagenase. Our theoretical results and MM/GBSA binding free energy calculations are consistent with experimental studies.
佐安他明类生物碱具有广泛的生物学效应。本研究旨在通过使用能量最小化、对接、分子动力学模拟和MM-PB/GBSA结合自由能计算对胶原酶处配体的三维结构进行建模，来研究去甲佐安他明及其十种佐安他明类同系物对人成纤维细胞胶原酶的抑制作用。结果表明，佐安他酰胺、虫黄藻胺和去甲佐安他明的烯醇亚胺形式，其结合自由能低于其他化合物，是胶原酶的有效抑制剂。然而，去甲佐安他明的烯醇亚胺形式对胶原酶的抑制活性比其酮形式更强。这表明它可用于治疗许多疾病，如骨质疏松症、自身免疫性疾病和癌症。在设计胶原酶抑制剂时，应考虑参与氢键作用的锌结合残基，如His 118、His 122和His 128，以及参与疏水相互作用的Leu 81、Tyr 110、Val 115、Leu 126、Pro 138、Ser 139。我们的理论结果和MM/GBSA结合自由能计算与实验研究结果一致。
