Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
Centre for the Environment, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
Comb Chem High Throughput Screen. 2020;23(8):757-774. doi: 10.2174/1386207323666200428114216.
Matrix metalloproteinase 1 are zinc-dependent endopeptidases responsible for the controlled breakdown of the extracellular matrix resulting in the maintenance of homeostasis. Dysregulation of MMP1 leads to the progression of various pathological conditions like cancer, rheumatoid arthritis, cardiovascular disease, skin damage and fibrotic disorder. Thus, MMP1 inhibition is the potential drug target of many synthetic MMP1 inhibitors but lack of substrate specificity hinders their clinical applicability. Hence, inhibitors from natural products have gained widespread attention.
The present study attempts screening of novel MMP1 inhibitors from the ZINC database based on experimentally reported natural inhibitors of MMP1 as a scaffold.
Molecular docking study was performed with 19 experimentally reported natural inhibitors spanning across nine different classes followed by virtual screening using the selected compounds. The selected compounds were subjected to molecular dynamics simulation.
Twenty compounds were screened with a cut-off of -9.0 kcal/mol of predicted free energy of binding, which further converged to 6 hits after docking studies. After comparing the docking result of 6 screened hits, two best compounds were selected. ZINC02436922 had the best interaction with six hydrogen bond formation to a relatively confined region in the S1'site of MMP1 and -10.01 kcal/mol of predicted free energy of binding. ZINC03075557 was the secondbest compound with -9.57 kcal/mol predicted binding free energy. Molecular dynamics simulation of ZINC02436922 and ZINC03075557 corroborates docking study.
This study indicated phenolic compounds ZINC02436922 and ZINC03075557 as potential MMP1 inhibitors.
基质金属蛋白酶 1 是锌依赖性内肽酶，负责细胞外基质的受控分解，从而维持内环境稳定。MMP1 的失调导致各种病理状况的进展，如癌症、类风湿性关节炎、心血管疾病、皮肤损伤和纤维化疾病。因此，MMP1 抑制是许多合成 MMP1 抑制剂的潜在药物靶点，但缺乏底物特异性阻碍了它们的临床应用。因此，天然产物抑制剂引起了广泛关注。
本研究试图基于实验报道的 MMP1 天然抑制剂作为支架，从 ZINC 数据库中筛选新型 MMP1 抑制剂。
对 19 种实验报道的天然 MMP1 抑制剂进行分子对接研究，涵盖 9 个不同类别，然后使用选定的化合物进行虚拟筛选。选择的化合物进行分子动力学模拟。
筛选出 20 种化合物，其结合自由能预测值为-9.0 kcal/mol，经过对接研究后进一步收敛为 6 个命中物。比较 6 个筛选出的命中物的对接结果后，选择了两个最佳化合物。ZINC02436922 与 MMP1 的 S1' 位点相对受限区域形成 6 个氢键，结合自由能预测值为-10.01 kcal/mol。ZINC03075557 是第二个最佳化合物，预测结合自由能为-9.57 kcal/mol。ZINC02436922 和 ZINC03075557 的分子动力学模拟证实了对接研究的结果。
本研究表明酚类化合物 ZINC02436922 和 ZINC03075557 可能是 MMP1 的抑制剂。
