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High-Throughput Docking and Molecular Dynamics Simulations towards the Identification of Potential Inhibitors against Human Coagulation Factor XIIa.
Computational and Mathematical Methods in Medicine ( IF 2.809 ) Pub Date : 2020-05-22 , DOI: 10.1155/2020/2852051
Dongfang Xu 1 , Guangpu Xue 2 , Bangya Peng 3 , Zanjie Feng 3 , Hongling Lu 3 , Lihu Gong 3
Affiliation  

Human coagulation factor XIIa (FXIIa) is a trypsin-like serine protease that is involved in pathologic thrombosis. As a potential target for designing safe anticoagulants, FXIIa has received a great deal of interest in recent years. In the present study, we employed virtual high-throughput screening of 500,064 compounds within Enamine database to acquire the most potential inhibitors of FXIIa. Subsequently, 18 compounds with significant binding energy (from -65.195 to -15.726 kcal/mol) were selected, and their ADMET properties were predicted to select representative inhibitors. Three compounds (Z1225120358, Z432246974, and Z146790068) exhibited excellent binding affinity and druggability. MD simulation for FXIIa-ligand complexes was carried out to reveal the stability and inhibition mechanism of these three compounds. Through the inhibition of activated factor XIIa assay, we tested the activity of five compounds Z1225120358, Z432246974, Z45287215, Z30974175, and Z146790068, with pIC50 values of , , , , and  M, respectively; the AMDET properties of Z45287215 and Z30974175 show not well but have better inhibition activity. We also found that compounds Z1225120358, Z45287215, Z30974175, and Z146790068 could be more inhibition of FXIIa than Z432246974. Collectively, compounds Z1225120358, Z45287215, Z30974175, and Z146790068 were anticipated to be promising drug candidates for inhibition of FXIIa.

中文翻译:

高通量对接和分子动力学模拟,用于识别潜在的抗人凝血因子XIIa抑制剂。

人凝血因子XIIa(FXIIa)是一种胰蛋白酶样丝氨酸蛋白酶,参与病理性血栓形成。FXIIa作为设计安全抗凝剂的潜在目标,近年来受到了广泛的关注。在本研究中,我们在Enamine数据库中对500,064种化合物进行了虚拟高通量筛选,以获取最具潜力的FXIIa抑制剂。随后,选择了18种具有显着结合能(-65.195至-15.726 kcal / mol)的化合物,并预测它们的ADMET特性将选择代表性的抑制剂。三种化合物(Z1225120358,Z432246974和Z146790068)表现出出色的结合亲和力和药物可塑性。进行了FXIIa-配体复合物的MD模拟,以揭示这三种化合物的稳定性和抑制机理。  M分别;Z45287215和Z30974175的AMDET特性显示不佳,但具有更好的抑制活性。我们还发现,化合物Z1225120358,Z45287215,Z30974175和Z146790068比Z432246974对FXIIa的抑制作用更大。总体上,化合物Z1225120358,Z45287215,Z30974175和Z146790068有望成为抑制FXIIa的有前途的候选药物。
更新日期:2020-05-22
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