β-Carboline alkaloids induce structural plasticity and inhibition of SARS-CoV-2 nsp3 macrodomain more potently than remdesivir metabolite GS-441524: computational approach

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 beta-Carboline (beta C) alkaloids. In this study, 1497 beta C analogues from the HiT2LEAD chemical database were screened, using computational approaches of Glide XP docking, molecular dynamics simulation and pk-CSM ADMET predictions. Selectively, beta C 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 beta C 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.

Automated summary

The study screened 1497 beta C analogues and found that beta C ligands 129, 584, 1303, and 1323 showed higher binding affinities to the receptor, suggesting their potential as promising anti-SARS-CoV-2 candidates.