Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease

Abstract

To fight against the devastating coronavirus disease 2019 (COVID-19), identifying robust anti-SARS-CoV-2 therapeutics from all possible directions is necessary. To contribute to this effort, we selected a human metabolites database containing waters and lipid-soluble metabolites to screen against the 3-chymotrypsin-like proteases (3CL pro ) protein of SARS-CoV-2. The top 8 hits from virtual screening displayed a docking score varying between ~ − 11 and ~ − 14 kcal/mol. Molecular dynamics simulations complement the virtual screening study in conjunction with the molecular mechanics generalized Born surface area (MM/GBSA) scheme. Our analyses revealed that (HMDB0132640) has the best glide docking score, − 14.06 kcal/mol, and MM-GBSA binding free energy, − 18.08 kcal/mol. The other three lead molecules are also selected along with the top molecule through a critical inspection of their pharmacokinetic properties. HMDB0132640 displayed a better binding affinity than the other three compounds (HMDB0127868, HMDB0134119, and HMDB0125821) due to increased favorable contributions from the intermolecular electrostatic and van der Waals interactions. Further, we have investigated the ligand-induced structural dynamics of the main protease. Overall, we have identified new compounds that can serve as potential leads for developing novel antiviral drugs against SARS-CoV-2 and elucidated molecular mechanisms of their binding to the main protease. Graphical abstract Identification of probable hits from human metabolites against SARS-CoV-2 using integrated computational approaches-Missed against MS Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10513-6.

4″-Alkyl EGCG Derivatives Induce Cytoprotective Autophagy Response by Inhibiting EGFR in Glioblastoma Cells

“…The molecular mechanics Poisson–Boltzmann surface area (MMPBSA) scheme was used to estimate the binding free energy of all protein–ligand complexes. This method is widely used for estimating the binding free energy of various biomolecular complexes. − Frames were used from the last 200 ns of the trajectories, and the binding energy was estimated using the following equation normalΔ G normalb normali normaln normald = Δ H − T normalΔ S ≈ normalΔ E normali normaln normalt normale normalr normaln normala normall + normalΔ G normals normalo normall normalv − T normalΔ S …”

“…The molecular mechanics Poisson–Boltzmann surface area (MMPBSA) scheme was used to estimate the binding free energy of all protein–ligand complexes. This method is widely used for estimating the binding free energy of various biomolecular complexes. − Frames were used from the last 200 ns of the trajectories, and the binding energy was estimated using the following equation …”

“…This method is widely used for estimating the binding free energy of various biomolecular complexes. 61 − 63 Frames were used from the last 200 ns of the trajectories, and the binding energy was estimated using the following equation. 64 …”

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“…Mpro's pivotal role in viral replication and the S protein's significance in mediating viral entry make them prime candidates for drug development. Computational investigations employing molecular docking and molecular dynamics (MD) simulations as well as virtual screening were instrumental in unveiling insights into the structural characteristics and dynamic behaviors of these proteins [12][13][14][15][16][17][18][19][20][21][22][23]. These studies aimed to identify novel compounds that can selectively inhibit Mpro's enzymatic activity and disrupt the binding of the S protein to its host cell receptor.…”