Shahab Muhammad, Danial Muhammad, Khan Taimur, Liang Chaoqun, Duan Xiuyuan, Wang Daixi, Gao Hanzi, Zheng Guojun
State Key Laboratories of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing 100029, China.
Shenzhen Institute of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen 518055, China.
Biomedicines. 2023 Mar 21;11(3):961. doi: 10.3390/biomedicines11030961.
is an opportunistic Gram-negative bacterium implicated in acute and chronic nosocomial infections and a leading cause of patient mortality. infections are frequently associated with the development of biofilms, which give the bacteria additional drug resistance and increase their virulence. The goal of this study was to find strong compounds that block the Anthranilate-CoA ligase enzyme made by the pqsA gene. This would stop the quorum signaling system. This enzyme plays a crucial role in the pathogenicity of by producing autoinducers for cell-to-cell communication that lead to the production of biofilms. Pharmacophore-based virtual screening was carried out utilizing a library of commercially accessible enzyme inhibitors. The most promising hits obtained during virtual screening were put through molecular docking with the help of MOE. The virtual screening yielded 7/160 and 10/249 hits (ZINC and Chembridge). Finally, 2/7 ZINC hits and 2/10 ChemBridge hits were selected as potent lead compounds employing diverse scaffolds due to their high pqsA enzyme binding affinity. The results of the pharmacophore-based virtual screening were subsequently verified using a molecular dynamic simulation-based study (MDS). Using MDS and post-MDS, the stability of the complexes was evaluated. The most promising lead compounds exhibited a high binding affinity towards protein-binding pocket and interacted with the catalytic dyad. At least one of the scaffolds selected will possibly prove useful for future research. However, further scientific confirmation in the form of preclinical and clinical research is required before implementation.
是一种机会性革兰氏阴性菌，与急性和慢性医院感染有关，是患者死亡的主要原因。感染常常与生物膜的形成相关，生物膜赋予细菌额外的耐药性并增加其毒力。本研究的目的是找到能够阻断由pqsA基因产生的邻氨基苯甲酸 - CoA连接酶的强效化合物。这将阻断群体感应信号系统。该酶通过产生用于细胞间通讯的自诱导物，在生物膜的产生中发挥关键作用，从而在的致病性中起关键作用。利用可商购的酶抑制剂库进行基于药效团的虚拟筛选。在虚拟筛选过程中获得的最有前景的命中物在MOE的帮助下进行分子对接。虚拟筛选产生了7/160和10/249个命中物（ZINC和Chembridge）。最后，由于其对pqsA酶的高结合亲和力，2/7个ZINC命中物和2/10个ChemBridge命中物被选为采用不同支架的强效先导化合物。基于药效团的虚拟筛选结果随后使用基于分子动力学模拟的研究（MDS）进行验证。使用MDS和MDS后，评估复合物的稳定性。最有前景的先导化合物对蛋白质结合口袋表现出高结合亲和力，并与催化二元组相互作用。所选的至少一种支架可能对未来的研究有用。然而，在实施之前需要以临床前和临床研究的形式进行进一步的科学确认。
