Abstract

Osteoarthritis (OA) is a degenerative disease which affects a large number of individuals. Collagenases, which belong to a class of metalloproteases (MMPs), are responsible for the degradation of cartilage manifested in OA. Inhibition of the catalytic domains of these MMPs is one of the important therapeutic strategies proposed for the prevention of OA. The main objective of this work is to evaluate the binding of curcumin and its metabolites with the active sites of collagenases in comparison to standard inhibitors on the basis of our hypothesis that curcumin/metabolites could exhibit an inhibitory effect on MMPs. Here, we report the molecular docking analysis of curcumin and its metabolites with collagenases (MMP-1, MMP-8, MMP-13). Among the molecules tested, curcumin monoglucuronide (CMG) demonstrated the best binding affinity with MMP-13, which is specifically implicated in OA. The CMG–MMP-complexes were further subjected to molecular dynamic simulations to explore the stability of the complexes and to estimate the free binding energies. The results indicated that CMG preferentially bind to MMP-13 in comparison to that of MMP-1 and MMP-8 with binding free energies (ΔG_bind) of (−60.55), (−27.02) and (−46.91) kcal/mol, respectively. This is the first study which suggests that curcumin monoglucuronide can be considered as an effective lead compound to prevent the progression of OA.

Communicated by Ramaswamy H. Sarma

摘要

骨关节炎 (OA) 是一种影响大量个体的退行性疾病。胶原酶属于一类金属蛋白酶 (MMP)，负责 OA 中表现出的软骨降解。抑制这些 MMP 的催化结构域是为预防 OA 提出的重要治疗策略之一。这项工作的主要目的是根据我们的假设，即姜黄素/代谢物可能对 MMP 表现出抑制作用，与​​标准抑制剂相比，评估姜黄素及其代谢物与胶原酶活性位点的结合。在这里，我们报告姜黄素及其代谢物与胶原酶（MMP-1、MMP-8、MMP-13）的分子对接分析。在测试的分子中，姜黄素单葡糖苷酸 (CMG) 与 MMP-13 的结合亲和力最好，这特别涉及OA。进一步对 CMG-MMP 配合物进行分子动力学模拟，以探索配合物的稳定性并估计自由结合能。结果表明，与具有结合自由能的 MMP-1 和 MMP-8 相比，CMG 优先与 MMP-13 结合（ΔG_{分别为 ( -60.55} )、(-27.02) 和 (-46.91) kcal/mol。这是第一项表明姜黄素单葡糖苷酸可被视为预防 OA 进展的有效先导化合物的研究。

由 Ramaswamy H. Sarma 传达