Ai Xianjie, Wang Xinyu, Ren Taotao, Li Zhong, Wu Bo, Li Ming
Lower Extremity Division, Orthopedic Trauma Department, Honghui Hospital, Xi'an Jiaotong University Youyi East Road No. 555, Beilin District, Xi'an, Shaanxi, China.
Department of Orthopaedic Trauma, Center of Orthopaedics and Traumatology, The First Hospital of Jilin University Street Xinmin 71, Changchun, Jilin, China.
Am J Transl Res. 2024 Nov 15;16(11):7071-7086. doi: 10.62347/NXMR6806. eCollection 2024.
The stromal cell protein metalloproteinase 9 (MMP9), associated with extracellular matrix degradation and remodeling, promotes tumor invasion and metastasis and regulates cell adhesion molecule and cytokine activity. This study evaluated MMP9 in pan-cancer and screened for compounds and drug candidates that can inhibit it.
MMP9 expression in pan-cancer tissues was evaluated in a pan-cancer dataset from the University of California Santa Cruz database, along with the correlation between MMP9 and the tumor microenvironment (TME), RNA modification genes, and tumor mutation burden. MMP9 crystal structures were downloaded, and a ligand-based pharmacophore model was constructed. A machine learning model was constructed for further screening. The identified compounds were pooled into Discovery Studio 4.5 for absorption, distribution, metabolism, and excretion (ADME) and toxicity prediction. Molecular docking was used to demonstrate the binding affinity and mechanism between the compounds and MMP9, and the stability of the ligand-receptor complex was assessed.
The expression levels of MMP9 differed between tumor tissues. Prognostic analysis showed that high MMP9 expression indicates poor survival and tumor progression in glioma (GMBLGG), pan-kidney (KIPAN; KICH+KIRC+KIRP), uveal melanoma (UVM), low-grade glioma (LGG), adrenocortical carcinoma (ACC), and liver hepatocellular carcinoma (LIHC). MMP9 expression in GMBLGG, KIPAN, UVM, LGG, ACC, and LIHC was positively correlated with the TME. The ligand-based pharmacophore model and the machine learning model identified 49 small molecules. ADME and toxicity prediction identified CEMBL82047 and CEMBL381163 as potential MMP9 inhibitors, showing robust binding affinity with MMP9. The resulting complexes are stable in the natural environment.
CHEMBL82047 and CHEMBL381163 are ideal compounds for inhibiting MMP9. The findings of this study will contribute to the design and improvement of MMP9-targeting drugs.
基质细胞蛋白金属蛋白酶9（MMP9）与细胞外基质降解和重塑相关，可促进肿瘤侵袭和转移，并调节细胞粘附分子和细胞因子活性。本研究评估了MMP9在泛癌中的情况，并筛选了可抑制它的化合物和候选药物。
在来自加利福尼亚大学圣克鲁兹数据库的泛癌数据集中评估MMP9在泛癌组织中的表达，以及MMP9与肿瘤微环境（TME）、RNA修饰基因和肿瘤突变负担之间的相关性。下载MMP9晶体结构，并构建基于配体的药效团模型。构建机器学习模型进行进一步筛选。将鉴定出的化合物汇集到Discovery Studio 4.5中进行吸收、分布、代谢和排泄（ADME）以及毒性预测。使用分子对接来证明化合物与MMP9之间的结合亲和力和机制，并评估配体-受体复合物的稳定性。
肿瘤组织中MMP9的表达水平有所不同。预后分析表明，MMP9高表达表明神经胶质瘤（GMBLGG）、全肾（KIPAN；KICH+KIRC+KIRP）、葡萄膜黑色素瘤（UVM）、低级别神经胶质瘤（LGG）、肾上腺皮质癌（ACC）和肝细胞肝癌（LIHC）患者的生存率较低且肿瘤进展。GMBLGG、KIPAN、UVM、LGG、ACC和LIHC中MMP9的表达与TME呈正相关。基于配体的药效团模型和机器学习模型鉴定出49种小分子。ADME和毒性预测确定CEMBL82047和CEMBL381163为潜在的MMP9抑制剂，显示出与MMP9有强大的结合亲和力。所形成的复合物在自然环境中稳定。
CHEMBL82047和CHEMBL381163是抑制MMP9的理想化合物。本研究结果将有助于设计和改进靶向MMP9的药物。
