Compounds from myrtle flowers as antibacterial agents and SARS-CoV-2 inhibitors: In-vitro and molecular docking studies

We provide promising computational (in silico) data on phytochemicals (compounds 1–10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1–10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1–10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests.

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

Saquib,

Bakheit,

Ahmed

et al. 2024

“…To explore the inhibition mechanism with binding energies of the synthesized compound towards the antibacterial proteins from Escherichia coli and Pseudomonas aeruginosa pathgenic strains, molecular docking simulations were properly carried out, whose the active molecule was initially docked to the crystal structure of an Escherichia coli protein (resolution of 2.30 Å) encoded as 1KZN.pdb [ 57 ], with a binding energy of −6.22 kcal/mol, forming a variety of intermolecular interactions, including one Hydrogen bond detected with the ASN 46 amino acid residue; one Pi-anion chemical bond with the Asp 49 amino acid residue; and more than three Pi-Alkyl bonds produced towards the Ala 47, Ala 53, and Ile 78 amino acid residues in the A chain, as presented in Figure 3 .…”

Section: Resultsmentioning

confidence: 99%

“…whose the active molecule was initially docked to the crystal structure of an Escherichia coli protein (resolution of 2.30 Å) encoded as 1KZN.pdb [57], with a binding energy of −6.22 kcal/mol, forming a variety of intermolecular interactions, including one Hydrogen bond detected with the ASN 46 amino acid residue; one Pi-anion chemical bond with the Asp 49 amino acid residue; and more than three Pi-Alkyl bonds produced towards the Ala 47, Ala 53, and Ile 78 amino acid residues in the A chain, as presented in Figure 3. The studied compound was docked for the second time towards the crystal structure of a penicillin-binding protein from Pseudomonas aeruginosa (resolution of 2.01 Å) encoded as 4KQR.pdb [58], with a binding energy of −6.05 kcal/mol, producing a family of chemical bonds, including one Hydrogen bond detected towards the Tyr 407 amino acid residue and one Pi-cation bond fixed with the Arg 331 amino acid residue, in addition to two Pi-Pi T-shaped bonds which were created with the Tyr 409 and Tyr 498 amino acid residues in the A chain, as shown in Figure 4.…”

Section: Docking Molecular Studymentioning

confidence: 99%

New Triazole-Isoxazole Hybrids as Antibacterial Agents: Design, Synthesis, Characterization, In Vitro, and In Silico Studies

Bouzammit,

Belchkar,

El fadili

et al. 2024

Novel isoxazole–triazole conjugates have been efficiently synthesized using 3-formylchromone as starting material according to a multi-step synthetic approach. The structures of the target conjugates and intermediate products were characterized by standard spectroscopic techniques (1H NMR and 13C NMR) and confirmed by mass spectrometry (MS). The all-synthesized compounds were screened for their antibacterial activity against three ATCC reference strains, namely Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC BAA-44, and Escherichia coli ATCC 25922 as well as one strain isolated from the hospital environment Pseudomonas aeruginosa. The findings indicate that conjugate 7b exhibits a stronger antibacterial response against the tested Escherichia coli ATCC 25922 and Pseudomonas aeruginosa pathogenic strains compared to the standard antibiotics. Furthermore, hybrid compound 7b proved to have a bactericidal action on the Escherichia coli ATCC 25922 strain, as evidenced by the results of the MBC determination. Moreover, the ADMET pharmacokinetic characteristics revealed a favorable profile for the examined compound, as well as a good level of oral bioavailability. Molecular docking and molecular dynamics simulations were performed to explore the inhibition mechanism and binding energies of conjugate 7b with the proteins of Escherichia coli and Pseudomonas aeruginosa bacterial strains. The in silico results corroborated the data observed in the in vitro evaluation for compound 7b.

“…Hence, the ethnopharmacological value of this plant derives from its ubiquitously abundant phytochemicals, including poly(phenols), flavonoids, tannins, gallic acid, flavonol derivatives, hydroxybenzoic acids alkaloids, terpenoids, and quinonoids [ 30 ]. Under rigorous scientific scrutiny, promising antibacterial [ 31 ], anti-inflammatory [ 28 , 32 ], anticancer [ 33 ], antioxidant, antidiabetic [ 24 ], antigenotoxic [ 34 ], and antimicrobial activities [ 35 ] of M. communis were discovered with multi-component, multi-target, and multi-mechanism models, making it an ideal choice to be exploited for the development of novel therapies [ 36 ]. Myrtle has been deeply scrutinized by the research community, whereas in Algeria, the chemical profile and biological activities of myrtle leaves have not been explicitly investigated.…”

Section: Introductionmentioning

confidence: 99%

Chemical Composition Antioxidant and Anti-Inflammatory Activities of Myrtus communis L. Leaf Extract: Forecasting ADMET Profiling and Anti-Inflammatory Targets Using Molecular Docking Tools

Belahcene,

Kebsa,

Akingbade

et al. 2024

Compounds derived from natural sources continue to serve as chemical scaffolds for designing prophylactic/therapeutic options for human healthcare. In this study, we aimed to systematically unravel the chemical profile and antioxidant and anti-inflammatory activities of myrtle methanolic extract (MMEx) using in vitro, in vivo, and in silico approaches. High levels of TPC (415.85 ± 15.52 mg GAE/g) and TFC (285.80 ± 1.64 mg QE/g) were observed. Mass spectrophotometry (GC-MS) analysis revealed the presence of 1,8-cineole (33.80%), α-pinene (10.06%), linalool (4.83%), p-dimethylaminobenzophenone (4.21%), thunbergol (4%), terpineol (3.60%), cis-geranyl acetate (3.25%), and totarol (3.30%) as major compounds. MMEx induced pronounced dose-dependent inhibition in all assays, and the best antioxidant activity was found with H2O2, with an IC50 of 17.81 ± 3.67 µg.mL−1. MMEx showed a good anti-inflammatory effect in vivo by limiting the development of carrageenan-induced paw edema. The pharmacokinetic profiles of the active molecules were determined using the SwissADME website, followed by virtual screening against anti-inflammatory targets including phospholipase A2 (PLA-2), cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and NF-κB. A pharmacokinetic study revealed that the molecules have good absorption, distribution, and metabolism profiles, with negative organ toxicity. Among the compounds identified by GC-MS analysis, pinostrobin chalcone, cinnamyl cinnamate, hedycaryol, totarol, and p-dimethylaminobenzophenone were observed to have good binding scores, thus appreciable anti-inflammatory potential. Our study reveals that MMEx from Algerian Myrtus communis L. can be considered to be a promising candidate for alleviating many health complaints associated with oxidative stress and inflammation.