Background: 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.

Objective: The present study attempts screening of novel MMP1 inhibitors from the ZINC database based on experimentally reported natural inhibitors of MMP1 as a scaffold.

Methods: 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.

Results: 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.

Conclusion: This study indicated phenolic compounds ZINC02436922 and ZINC03075557 as potential MMP1 inhibitors.

背景：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，从而维持体内稳态。MMP1的失调导致各种病理状况的发展，例如癌症，类风湿性关节炎，心血管疾病，皮肤损害和纤维化疾病。因此，MMP1抑制是许多合成MMP1抑制剂的潜在药物靶标，但是底物特异性的缺乏阻碍了它们的临床应用。因此，来自天然产物的抑制剂已受到广泛关注。

目的：本研究尝试以实验报告的MMP1天然抑制剂为支架，从ZINC数据库中筛选新型MMP1抑制剂。

方法：用19种实验报告的天然抑制剂进行分子对接研究，这些抑制剂跨越9种不同的类别，然后使用所选化合物进行虚拟筛选。对所选化合物进行分子动力学模拟。

结果：筛选了二十种化合物，其预测结合自由能的截断值为-9.0 kcal / mol，在对接研究后进一步收敛至6个命中点。在比较了6个筛选结果的对接结果后，选择了两个最佳化合物。ZINC02436922与六个氢键形成到MMP1的S1'位点的相对受限区域的相互作用最佳，预测结合能为-10.01 kcal / mol。ZINC03075557是第二好的化合物，预测的结合自由能为-9.57 kcal / mol。ZINC02436922和ZINC03075557的分子动力学模拟证实了对接研究。

结论：这项研究表明酚类化合物ZINC02436922和ZINC03075557是潜在的MMP1抑制剂。