Tamang Jigme Sangay Dorjay, Banerjee Suvankar, Ghosh Balaram, Baidya Sandip Kumar, Jha Tarun, Adhikari Nilanjan
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 Campus, Shamirpet, Hyderabad, 500078 India.
In Silico Pharmacol. 2025 Jan 7;13(1):10. doi: 10.1007/s40203-024-00296-z. eCollection 2025.
The implication of matrix metalloproteinase-12 (MMP-12) in various major disorders including cancer, COPD, cardiovascular disorders, and neurological diseases makes it a potential target for drug discovery. Contemplating the significance of MMP-12, a number of MMP-12 inhibitors were designed, synthesized and tested throughout the world but the non-selective nature of most of those molecules can lead to adverse drug interactions. In contradiction, the dibenzofuran (DBF) and dibenzothiophene (DBT) derivatives showed highly potent and selective MMP-12 inhibition. Therefore, to identify the prime molecular and structural attributes that are affecting the MMP-12 inhibitory activity, the linear discriminant analysis (LDA), Bayesian classification, recursive partitioning, and SARpy analysis were performed to extract the prime attributes of these DBFs and DBTs affecting MMP-12 inhibition. These studies suggested that substructures like isopropyl carboxylic acid, 5-methyl furan, 1,2,4-oxadiazole, and DBT moieties can impart moderate to high contribution for MMP-12 inhibition. Importantly, the outcomes of the current studies were also in agreement with our regression-based study performed earlier. Furthermore, the molecular docking-mediated virtual screening of DBT and DBF analogs of the ChEMBL database demonstrated the viability of other DBT and DBF analogs to become potential MMP-12-selective inhibitors. The molecular dynamics (MD) simulation study of hit molecules also showed the potential of the combination of phosphonic acid ZBG and DBF P1' substituent for effective anchoring/binding at the MMP-12 active site. Therefore, the findings may help in the discovery and designing of novel MMP-12 inhibitors that may be used for the treatment of various pathological diseases including cancer and COPD.
The online version contains supplementary material available at 10.1007/s40203-024-00296-z.
基质金属蛋白酶-12（MMP-12）在包括癌症、慢性阻塞性肺疾病（COPD）、心血管疾病和神经疾病在内的各种主要疾病中的作用使其成为药物研发的潜在靶点。鉴于MMP-12的重要性，世界各地设计、合成并测试了多种MMP-12抑制剂，但其中大多数分子的非选择性可能导致不良药物相互作用。与之相反，二苯并呋喃（DBF）和二苯并噻吩（DBT）衍生物表现出高效且选择性的MMP-12抑制作用。因此，为了确定影响MMP-12抑制活性的主要分子和结构特征，进行了线性判别分析（LDA）、贝叶斯分类、递归划分和SARpy分析，以提取这些DBF和DBT影响MMP-12抑制的主要特征。这些研究表明，异丙基羧酸、5-甲基呋喃、1,2,4-恶二唑和DBT部分等亚结构对MMP-12抑制可产生中等至高贡献。重要的是，当前研究的结果也与我们之前基于回归的研究一致。此外，对ChEMBL数据库中DBT和DBF类似物进行的分子对接介导的虚拟筛选表明，其他DBT和DBF类似物有成为潜在MMP-12选择性抑制剂的可能性。对命中分子的分子动力学（MD）模拟研究还表明，膦酸锌结合基团（ZBG）和DBF P1'取代基的组合在MMP-12活性位点有效锚定/结合的潜力。因此，这些发现可能有助于发现和设计可用于治疗包括癌症和COPD在内的各种病理疾病的新型MMP-12抑制剂。
在线版本包含可在10.1007/s40203-024-00296-z获取的补充材料。
