药效团
化学
广告
数量结构-活动关系
变构调节
生物信息学
吡啶
对接(动物)
药物设计
组合化学
合理设计
立体化学
小分子
药物发现
分子模型
计算化学
酶
生物化学
纳米技术
有机化学
体外
医学
材料科学
护理部
基因
作者
Ossama Daoui,Souad Elkhattabi,Samir Chtita
标识
DOI:10.1016/j.molstruc.2022.133964
摘要
Research efforts to develop an effective drug for lymphoma with minimal side effects are still very slow. To aid the discovery of new lymphoma drug, we led an extensive in silico computational study based on pharmacophore QSAR modeling, DFT, Molecular Docking, ADME-Tox, biophysical simulation approaches such as Molecular Dynamics analysis (MD) and comprehensive MM-GBSA free binding energy computations on a novel series of pyridine derivatives as promising MALT1 allosteric inhibitors (PDB code: 4I1R). The developed QSAR models demonstrated a strong correlation between the 2D/3D structural properties of pyridine derivatives and their biological inhibitory activity against MALT1 protease enzymatic activity. Based on detailed structural characterizations provided by the QSAR modeling, the biological inhibitory activity of four novel small molecules derived from the template molecule S40 (pIC50 = 8.00) was improved. Based on the molecular modeling and computer-aided drug design approaches used in this work, the lead novel compounds C2 (pIC50 > 8, BE = -9.4 kcal/mol, ΔGbind = -58.15 kcal/mol) and C3 (pIC50 > 8, BE = -8.7 kcal/mol, ΔGbind = -51.31 kcal/mol) were identified as optimal candidate allosteric inhibitors for MALT1 compared to the synthesized templates molecules S40 and Thioridazine. Finally, biophysical simulations demonstrated the high stability of the modeled ligands C2 and C3 inside the active pocket of the MALT1 protease in aqueous conditions throughout the 100 ns trajectory of the MD simulations. Thus, small designed hit compounds C2 and C3 can be used as valid references for design new drugs for lymphoma therapy by targeting MALT1 protease enzymatic activity.
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