Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad, India.
SAR QSAR Environ Res. 2023 Apr;34(4):299-319. doi: 10.1080/1062936X.2023.2209737. Epub 2023 May 12.
Among various matrix metalloproteinases (MMPs), overexpression of MMP9 has been established as a key player in a variety of cancers. Therefore, MMP9 has emerged as a promising biomolecule that may be targeted to design potent inhibitors as novel anticancer therapeutics. In this study, a large database containing 1,123 drug-like MMP-9 inhibitors was considered for robust classification-dependent fragment-based QSAR study through SARpy, Bayesian classification, and recursive partitioning analyses and were validated by both internal and external validation techniques. In a nutshell, all these classification-dependent techniques revealed some common structural alerts and sub-structural fingerprints responsible for modulating MMP-9 inhibition. These observations are in agreement with the interactions obtained from the ligand-bound co-crystal structures of MMP-9 justifying the robustness of the current study. Finally, based on these crucial structural fragments, some new lead compounds were designed and further validated by the binding mode of interaction analysis. Therefore, these findings may be beneficial in designing novel and potential MMP-9 inhibitors in the future as a weapon to combat several cancers.
在各种基质金属蛋白酶（MMPs）中，MMP9 的过表达已被确定为多种癌症的关键因素。因此，MMP9 已成为一种有前途的生物分子，可作为设计强效抑制剂的新抗癌治疗方法的靶点。在这项研究中，通过 SARpy、贝叶斯分类和递归分区分析，对包含 1123 种类药性 MMP-9 抑制剂的大型数据库进行了稳健的分类相关基于片段的 QSAR 研究，并通过内部和外部验证技术进行了验证。简而言之，所有这些分类相关技术都揭示了一些常见的结构警示和亚结构指纹，这些结构警示和亚结构指纹负责调节 MMP-9 的抑制作用。这些观察结果与从 MMP-9 的配体结合共晶结构中获得的相互作用一致，证明了当前研究的稳健性。最后，基于这些关键结构片段，设计了一些新的先导化合物，并通过结合模式相互作用分析进一步验证。因此，这些发现可能有助于未来设计新型和潜在的 MMP-9 抑制剂，作为对抗多种癌症的武器。
