Promising SARS-CoV-2 main protease inhibitor ligand-binding modes evaluated using LB-PaCS-MD/FMO

Abstract

Parallel cascade selection molecular dynamics-based ligand binding-path sampling (LB-PaCS-MD) was combined with fragment molecular orbital (FMO) calculations to reveal the ligand path from an aqueous solution to the SARS-CoV-2 main protease (Mpro) active site and to customise a ligand-binding pocket suitable for delivering a potent inhibitor. Rubraxanthone exhibited mixed-inhibition antiviral activity against SARS-CoV-2 Mpro, relatively low cytotoxicity, and high cellular inhibition. However, the atomic inhibition mechanism remains ambiguous. LB-PaCS-MD/FMO is a hybrid ligand-binding evaluation method elucidating how rubraxanthone interacts with SARS-CoV-2 Mpro. In the first step, LB-PaCS-MD, which is regarded as a flexible docking, efficiently samples a set of ligand-binding pathways. After that, a reasonable docking pose of LB-PaCS-MD is evaluated by the FMO calculation to elucidate a set of protein–ligand interactions, enabling one to know the binding affinity of a specified ligand with respect to a target protein. A possible conformation was proposed for rubraxanthone binding to the SARS-CoV-2 Mpro active site, and allosteric inhibition was elucidated by combining blind docking with k-means clustering. The interaction profile, key binding residues, and considerable interaction were elucidated for rubraxanthone binding to both Mpro sites. Integrated LB-PaCS-MD/FMO provided a more reasonable complex structure for ligand binding at the SARS-CoV-2 Mpro active site, which is vital for discovering and designing antiviral drugs.

N-Containing α-Mangostin Analogs via Smiles Rearrangement as the Promising Cytotoxic, Antitrypanosomal, and SARS-CoV-2 Main Protease Inhibitory Agents

“…The binding pattern of the xanthone core structure of these compounds is likely aligned into the same binding pocket (S1, S2, and S1′) at the 3CL pro active site ( Figure 4 B). The similar arrangement of these compounds in the active site is congruent to one of the best binding patterns of rubraxanthone in the previous report [ 39 ]. This core structure at the methoxy group at C–7 and the prenyl group at C–8 mainly interacted with the residues 41–45 in the S2 subpocket by dispersion ( ) and charge-transfer and mix terms ( ), referring to the hydrophobic interactions.…”

“…The crystal structure of SARS-CoV-2 3CL pro in complex with a noncovalent inhibitor (X77) derived from the protein databank (PDB code: 6W63) [ 46 ] was used to generate the complex structure with a potent compound by using the molecular docking [ 47 , 48 ] and subsequent FMO calculation according to the standard protocols used in our previous studies [ 39 , 49 ]. The 3D structures of potent compounds; α-mangostin ( 1 ), analogs 2 , and 4 were constructed using GaussView6 software and structurally optimized by the B3LYP/6-31G* level of theory by the Gaussian16 program [ 50 ].…”

Identification of Promising Sulfonamide Chalcones as Inhibitors of SARS-CoV-2 3CLpro through Structure-Based Virtual Screening and Experimental Approaches

“…Additionally, hydrophobic interactions explained by Δ E ij DI were observed in T25, T45, M49, and N142, interacting with the aromatic moiety of SWC423, confirming the importance of these interactions in keeping the compound in the binding pocket. The S−π interaction between M49 and the aromatic ring of SWC423 was also found to contribute to the binding stability of the system, which is similar to previously reported findings . However, repulsion effects were discovered in L27, E47, G146, E166, A173, and D187 (PIEDA > 10 kcal/mol) mainly through Δ E ij ES , which could be associated with the arrangement of the ligand in the active site.…”

“…The protocol for FMO-RIMP2/PCM in this study was similar to the previously described. 59,80 ■ ASSOCIATED CONTENT…”

Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors

“…The PIE of the consensus residues of EGFR within a 7 Å radius of SIQ17 was determined by calculating the electronic energy componentselectrostatic interaction ( E ij ES ), charge transfer with higher-order mixed term energies ( E ij CT+mix ), dispersion interaction ( E ij DI ), and exchange-repulsion energy ( E ij EX )between each pair of the fragment (i and j). This was done by using the resolution-of-the-identity second-order Møller–Plesset perturbation theory (RIMP2) combined with the PCM ( G Sol PCM ) to describe the solvation effects, as given in eq , which was implemented in the GAMESS software − PIE = normalΔ E italicij ES + normalΔ E italicij CT + mix + normalΔ E italicij DI + normalΔ E italicij EX + normalΔ G italicSol PCM …”