Exploration of natural compounds with anti-SARS-CoV-2 activityviainhibition of SARS-CoV-2 Mpro

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a dreaded pandemic in lack of specific therapeutic agent. SARS-CoV-2 Mpro, an essential factor in viral pathogenesis, is recognized as a prospective therapeutic target in drug discovery against SARS-CoV-2. To tackle this pandemic, Food and Drug Administration-approved drugs are being screened against SARS-CoV-2 Mpro via in silico and in vitro methods to detect the best conceivable drug candidates. However, identification of natural compounds with anti-SARS-CoV-2 Mpro potential have been recommended as rapid and effective alternative for anti-SARS-CoV-2 therapeutic development. Thereof, a total of 653 natural compounds were identified against SARS-CoV-2 Mpro from NP-lib database at MTi-OpenScreen webserver using virtual screening approach. Subsequently, top four potential compounds, i.e. 2,3-Dihydroamentoflavone (ZINC000043552589), Podocarpusflavon-B (ZINC000003594862), Rutin (ZINC000003947429) and Quercimeritrin 6”-O-L-arabinopyranoside (ZINC000070691536), and co-crystallized N3 inhibitor as reference ligand were considered for stringent molecular docking after geometry optimization by DFT method. Each compound exhibited substantial docking energy >−12 kcal/mol and molecular contacts with essential residues, including catalytic dyad (His41 and Cys145) and substrate binding residues, in the active pocket of SARS-CoV-2 Mpro against N3 inhibitor. The screened compounds were further scrutinized via absorption, distribution, metabolism, and excretion - toxicity (ADMET), quantum chemical calculations, combinatorial molecular simulations and hybrid QM/MM approaches. Convincingly, collected results support the potent compounds for druglikeness and strong binding affinity with the catalytic pocket of SARS-CoV-2 Mpro. Hence, selected compounds are advocated as potential inhibitors of SARS-CoV-2 Mpro and can be utilized in drug development against SARS-CoV-2 infection.

Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies

“…DFT based approaches were applied to a large set of pyridine N-oxide compounds as potential inhibitors of SARS-CoV-2 M Pro , peptidic Michael acceptor compounds, as well as to small molecule Schiff bases [115][116][117]. Moreover, SARS-2 M Pro was virtually screened for inhibition by several hundred natural compounds [118]. Using DFT calculations treated by B3LYP/6-31G(d,p) flavonoid disaccharides, such as rutin, yielded the highest re-docking energy.…”

Drug repurposing for ligand-induced rearrangement of Sirt2 active site-based inhibitors via molecular modeling and quantum mechanics calculations

“…Characteristically, ΔE MM represents the collection of the intermolecular energy (ΔE Int ), the electrostatic energy (ΔE Ele ), and the van der Waals interactions (ΔE vdW ) while ΔG Sol marked for the total sum of polar (ΔG Pol ) and non-polar (ΔG Nonpol ) energies of the whole system under consideration. Hence, the binding free energy was computed for each docked protein–ligand complex under default parameters using Prime MM/GBSA module in Maestro-Schrödinger suite 2019.2 35 , 37 , as reported earlier 45 , 46 .…”

“…Following 100 ns MD simulation of screened complexes of Sirt2-drugs, poses were extracted at every 10 ps from the last 10 ns simulation trajectory of each complex for end-point binding free energy calculation via Prime MMGBSA module of the MM/GBSA protocol in Schrödinger suite 2019–2 35 , as mentioned in section “Molecular mechanics/generalized Born surface area calculation”. Herein, net binding free energy was computed under default parameters on the extracted snapshots from respective simulated systems, where protein–ligand complexes were processed by removal of counter ions and solvent molecules (TIP4P) 46 , 54 .…”

“…Herein, Sirt2-Nintedanib complex (− 105.58 ± 7.28 kcal/mol) was established with the most significant end-point free binding energy among the selected Sirt2-drug docked complexes in reference to Sirt2-SirReal2 inhibitor complex (− 99.82 ± 5.21 kcal/mol). Also, as compared to docking scores and binding free energy values, the ranking performance of the screened ligands can be improved by quantum mechanics (QM) treatment on the ligands 46,74 . Besides, a combination of QM/MM molecular docking protocols [85][86][87] and MM/GBSA calculations was recently employed to reproduce the crystal structure geometries of protein-ligand complexes with halogen bonding 88 .…”

“…Besides, a combination of QM/MM molecular docking protocols [85][86][87] and MM/GBSA calculations was recently employed to reproduce the crystal structure geometries of protein-ligand complexes with halogen bonding 88 . Also, it has been shown that the prediction of the binding energy can be improved by utilizing dispersion corrected functional for the high-level quantum mechanical calculations as compared to commonly used methods such as B3LYP/DFT and MP2/DFT calculations 46 . Hence, final MD snapshots of the simulated complexes were studied by hybrid QM/MM binding energy, where the ligand-bound region was treated with WB97XD/6-31G** density functional to estimate the non-covalent electronic interaction energies while MM/ UFF force field was used for the protein environment.…”