The nsp3 macrodomain is implicated in the viral replication, pathogenesis and host immune responses through the removal of ADP-ribosylation sites during infections of coronaviruses including the SARS-CoV-2. It has ever been modulated by macromolecules including the ADP-ribose until Ni and co-workers recently reported its inhibition and plasticity enhancement unprecedentedly by remdesivir metabolite, GS-441524 , creating an opportunity for investigating other biodiverse small molecules such as β-Carboline (βC) alkaloids. In this study, 1497 βC analogues from the HiT2LEAD chemical database were screened, using computational approaches of Glide XP docking, molecular dynamics simulation and pk-CSM ADMET predictions. Selectively, βC ligands, 129, 584 , 1303 and 1323 demonstrated higher binding affinities to the receptor, indicated by XP docking scores of –10.72, –10.01, –9.63 and –9.48 kcal/mol respectively than remdesivir and GS-441524 with –4.68 and –9.41 kcal/mol respectively. Consistently, their binding free energies were –36.07, –23.77, –24.07 and –17.76 kcal/mol respectively, while remdesivir and GS-441524 showed –21.22 and –24.20 kcal/mol respectively. Interestingly, the selected βC ligands displayed better stability and flexibility for enhancing the plasticity of the receptor than GS-441524 , especially 129 and 1303 . Their predicted ADMET parameters favour druggability and low expressions for toxicity. Thus, they are recommended as promising adjuvant/standalone anti-SARS-CoV-2 candidates for further study. Key words : SARS-CoV-2, nsp3 macrodomain, ADP-ribose, β-carboline, bioinformatics, drug design
【저자키워드】 SARS-CoV-2, drug design, bioinformatics, nsp3 macrodomain, ADP-ribose, β-carboline, 【초록키워드】 coronavirus, Pathogenesis, Infection, Remdesivir, Toxicity, docking, binding free energy, anti-SARS-CoV-2, database, binding affinity, Molecular dynamics simulation, stability, Host immune response, viral replication, GS-441524, small molecule, Nsp3, receptor, metabolite, Ligand, ligands, low expression, macrodomain, candidate, plasticity, docking score, ADP-ribosylation, parameter, macromolecule, analogue, Glide, selected, predicted, reported, indicated, screened, demonstrated, implicated, modulated, computational approach, creating, the SARS-CoV-2, 【제목키워드】 Remdesivir, Nsp3, metabolite, macrodomain, plasticity, approach, induce,