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

Abstract

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.

Keywords: ADP-ribose; SARS-CoV-2; bioinformatics; drug design; nsp3 macrodomain; β-carboline.

Figure 1

Illustration of the ADP-ribose binding pocket of nsp3 macrodomain of SARS-CoV-2. (A) Plasticity of the ADP-ribose binding pocket; (B) Superimposition of eight molecules from the asymmetric units of two distinct apo crystal structures (PDBs 6YWK and 6YWM) (Reprinted with permission from (Ni et al., 2021), Copyright (2021) American Chemical Society; (C) 3D view of nssp3 Mac-1 in complex with G-441524 (PDB 7BF6); (D) Binding pose showing interactions of G-441524 with amino acids at the active ADP-ribose binding site.

Figure 2

Workflow of the study.

Figure 3

Binding poses showing interactions of selected βC ligands with conserved amino acid residues in the active pocket of SARS-CoV-2 nsp3 macrodomain (PDB 7BF6). Interactions are shown as hydrogen bonding (magenta arrow), π - cation (blue line), salt bridge (red line) and π - π stacking (green line).

Figure 4

Molecular dynamic simulation trajectories: (A) Statistics of H-bond contacts between the ligands and amino acid residues in the receptor; (B) RMSD of the receptor backbones and the ligands.

Figure 5

Molecular dynamics simulation results for the selected ligands in complexes SARS-CoV-2 nsp3 macrodomain. (A) The B-/ temperature factor of the selected βC ligands, remdesivir and the GS441524. The lowest fluctuations (Å) are observed with 1303 and 129, indicating the highest stability; (B) RMSF plot of the selected βC ligands and the references. Lower fluctuations are also demonstrated by βC ligands similarly to B-factor, inferring higher stability; (C) Plots of the radius of gyration ligand-receptor complex system. Lower fluctuations indicate more compactness and stability of the ligand-receptor system, relatively favouring βC ligands; (D) Native of contact and (Q) of the ligand-receptor complex. The larger the variations in Q, the more the rigidity of the receptor which is unfavourable for biological functions, especially involving binding of small molecule drugs. The selected βC ligands were also favoured relatively to remdesivir and GS-441524. (E) CABS-Flex RMSF of 129; (F) CABS-Flex RMSF of 129, indicating a reduced RMSF when the receptor was in complex with 129 compared to the complex involving GS-441524.

Figure 6

Time-dependent Apo protein RMSD (Å).

Figure 7

(A) RMSD (Protein RMSD is shown in grey while RMSD of 129 are shown in red) (B) RMSF and (C) 2d contact summary (D) Protein–ligand contact analysis of MD trajectory for 129 complex system.

Figure 8

(A) RMSD (Protein RMSD is shown in grey while RMSD of 1303 are shown in red). (B) RMSF and (C) 2d contact summary, (D) Protein–ligand contact analysis of MD trajectory for 1303 complex system.

Figure 9

Chemical structures of finally identified βC ligands with potentials for plasticity enhancement and inhibition of nsp3 macrodomain of SARS-CoV-2.