As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (2′OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (PDB ID: (6W4H) was conducted through a multi-step screening approach. At the beginning, molecular fingerprints experiment with SAM (S-Adenosylmethionine), the co-crystallized ligand of the targeted enzyme, unveiled the resemblance of 147 drugs. Then, a structural similarity experiment recommended 26 compounds. Therefore, the 26 compounds were docked against 2′OMTase to reveal the potential inhibitory effect of seven promising compounds (Protirelin, (1187), Calcium folinate (1913), Raltegravir (1995), Regadenoson (2176), Ertapenem (2396), Methylergometrine (2532), and Thiamine pyrophosphate hydrochloride (2612)). Out of the docked ligands, Ertapenem (2396) showed an ideal binding mode like that of the co-crystallized ligand (SAM). It occupied all sub-pockets of the active site and bound the crucial amino acids. Accordingly, some MD simulation experiments (RMSD, RMSF, R_g, SASA, and H-bonding) have been conducted for the 2′OMTase—Ertapenem complex over 100 ns. The performed MD experiments verified the correct binding mode of Ertapenem against 2′OMTase exhibiting low energy and optimal dynamics. Finally, MM-PBSA studies indicated that Ertapenem bonded advantageously to the targeted protein with a free energy value of −43 KJ/mol. Furthermore, the binding free energy analysis revealed the essential amino acids of 2′OMTase that served positively to the binding. The achieved results bring hope to find a treatment for COVID-19 via in vitro and in vivo studies for the pointed compounds.

Objective. This study aimed to investigate the preparation of patuletin-encapsulated chitosan nanoparticles (PT-CS-NPs) using the ionic gelation method, evaluate their potential as anticancer agents, and invent a new method of differential pulse voltammetric analysis for patuletin (PT). Methods. Computational studies were conducted to assess the affinity of PT for chitosan, confirming a promising interaction. PT-CS-NPs were synthesized based on the computational outputs, resulting in nanoparticles with an angular structure and an average size of 6.168 nm. The cytotoxicity of PT and PT-CS-NP was evaluated in breast and colon cancer cell lines, and selectivity indices were calculated to assess safety profiles. The electrochemical behavior of PT was also investigated using the Britton–Robinson buffer. Results. PT-CS-NP exhibited both potent cytotoxicity and a favorable safety profile, showing the most active and safest pattern of cytotoxicity among the tested compounds. The electrochemical oxidation of PT was observed at 0.531 V vs. Ag/AgCl at pH 4.0.0. The concentration of PT showed a linear relationship with the corresponding peak current over the range of M, with a minimum limit of detection of 3.4 × 10⁽⁻⁹⁾M. The proposed method successfully measured PT, with a relative standard deviation below 2%. Conclusion. The preparation of PT-CS-NP via the ionic gelation method resulted in angular nanoparticles with a promising anticancer activity and safety profiles. The electrochemical behavior of PT was characterized, and a reliable method for PT quantification was established.

Four compounds, hippacine, 4,2′-dihydroxy-4′-methoxychalcone, 2′,5′-dihydroxy-4-methoxychalcone, and wighteone, were selected from 4924 African natural metabolites as potential inhibitors against SARS-CoV-2 papain-like protease (PLpro, PDB ID: 3E9S). A multi-phased in silico approach was employed to select the most similar metabolites to the co-crystallized ligand (TTT) of the PLpro through molecular fingerprints and structural similarity studies. Followingly, to examine the binding of the selected metabolites with the PLpro (molecular docking. Further, to confirm this binding through molecular dynamics simulations. Finally, in silico ADMET and toxicity studies were carried out to prefer the most convenient compounds and their drug-likeness. The obtained results could be a weapon in the battle against COVID-19 via more in vitro and in vivo studies.

As a follow-up to our teamworks former work against SARS-CoV-2, eight compounds (ramelteon (68), prilocaine (224), nefiracetam (339), cyclandelate (911), mepivacaine (2325), ropivacaine (2351), tasimelteon (2384), and levobupivacaine (2840)) were revealed as the best potentially active SARS-CoV-2 inhibitors targeting the main protease (PDB ID: 5R84), M^pro. The compounds were named in the midst of 3009 FDA and clinically approved compounds employing a multistaged in silico method. A molecular fingerprints study with GWS, the cocrystallized ligand of the M^pro, indicated the resemblance of 150 candidates. Consequently, a structure similarity experiment disclosed the best twenty-nine analogous. Then, molecular docking studies were done against the M^pro active site and showed the binding of the best compounds. Next, a 3D-pharmacophore study confirmed the obtained results for the eight compounds by exhibiting relative fit values of more than 90 (except for 68, 74, and 2384, 83). Levobupivacaine (2840) showed the most accurate docking and pharmacophore scores and was picked for further MD simulations experiments (RMSD, RMSF, R_g, SASA, and H-H bonding) over 100ns. The MD simulations results revealed the accurate binding as well as the optimum dynamics of the M^pro-levobupivacaine complex. Finally, MM-PBSA studies were conducted and indicated the favorable bonding of the M^pro-levobupivacaine complex with a free energy value of 235kJ/mol. The fulfilled outcomes hold out hope of beating COVID-19 through more in vitro and in vivo research for the named compounds.