已设计并合成了一系列新的喹啉衍生物,作为可能的蛋白酶抑制剂(PIs)对抗严重急性呼吸综合征冠状病毒2。使用DSv20.1.0.19295软件的计算机模拟研究表明,这些化合物表现为PI,同时在目标Mpro酶(6LU7)的变构位点相互作用。设计的化合物显示了有希望的对接结果,这表明所有化合物都与His41,His164,Glu166,Tyr54,Asp187形成氢键,并显示与目标蛋白中高度保守的氨基酸His41的π相互作用。通过Komputer辅助技术进行的毒性预测结果证实,发现该化合物的毒性低于参考药物。Further,用蛋白酶对化合物5和remdesivir进行分子动力学模拟。构象稳定性分析,残留物的灵活性,紧密度,氢键,溶剂可及表面积(SASA),和结合自由能表明蛋白酶:5复合物与蛋白酶:remdesivir复合物的稳定性相当。氢键的结果表明,蛋白质残基(Glu166和Gln189)与配体5之间形成了大量的分子间氢键,验证了对接结果。Further,紧密度分析,SASA和类似氢键的相互作用证明化合物5的抑制性质类似于现有的参考药物。因此,设计的化合物5可能作为蛋白酶的潜在抑制剂。RamaswamyH.SarmaHighlightsQuinoline衍生物已被设计为针对SARS-CoV-2的蛋白酶抑制剂。将化合物停靠在SARS-CoV-2-Mpro酶(PDBID:6LU7)的变构位点,以研究蛋白质-配体复合物的稳定性。对接研究表明,所有设计的化合物都具有稳定的配体-蛋白质复合物。使用DSv20.1.0.19295软件中的Komputer辅助技术协议进行毒性预测,以评估设计的喹啉衍生物的毒性。分子动力学研究表明形成了稳定的配体-Mpro复合物。
A new series of quinoline derivatives has been designed and synthesized as probable protease inhibitors (PIs) against severe acute respiratory syndrome coronavirus 2. In silico studies using DS v20.1.0.19295 software have shown that these compounds behaved as PIs while interacting at the allosteric site of target Mpro enzyme (6LU7). The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with His41, His164, Glu166, Tyr54, Asp187, and showed π-interaction with His41, the highly conserved amino acids in the target protein. Toxicity Prediction by Komputer Assisted Technology results confirmed that the compounds were found to be less toxic than the reference drug. Further, molecular dynamics simulations were performed on compound 5 and remdesivir with protease enzyme. Analysis of conformational stability, residue flexibility, compactness, hydrogen bonding, solvent accessible surface area (SASA), and binding free energy revealed comparable stability of protease:5 complex to the protease: remdesivir complex. The result of hydrogen bonding showed a large number of intermolecular hydrogen bonds formed between protein residues (Glu166 and Gln189) and ligand 5, indicating strong interaction, which validated the docking result. Further, compactness analysis, SASA and interactions like hydrogen-bonding demonstrated inhibitory properties of compound 5 similar to the existing reference drug. Thus, the designed compound 5 might act as a potential inhibitor against the protease enzyme.Communicated by Ramaswamy H. SarmaHighlightsQuinoline derivatives have been designed as protease inhibitors against SARS-CoV-2.The compounds were docked at the allosteric site of SARS-CoV-2-Mpro enzyme (PDB ID: 6LU7) to study the stability of protein-ligand complex.Docking studies indicated the stable ligand-protein complexes for all designed compounds.The Toxicity Prediction by Komputer Assisted Technology protocol in DS v20.1.0.19295 software was used to evaluate the toxicity of the designed quinoline derivatives.Molecular dynamics studies indicated the formation of stable ligand-Mpro complexes.