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1.
Molecules ; 27(9)2022 May 04.
Article in English | MEDLINE | ID: covidwho-1820345

ABSTRACT

(1) Background: Natural constituents are still a preferred route for counteracting the outbreak of COVID-19. Essentially, flavonoids have been found to be among the most promising molecules identified as coronavirus inhibitors. Recently, a new SARS-CoV-2 B.1.1.529 variant has spread in many countries, which has raised awareness of the role of natural constituents in attempts to contribute to therapeutic protocols. (2) Methods: Using various chromatographic techniques, triterpenes (1-7), phenolics (8-11), and flavonoids (12-17) were isolated from Euphorbia dendroides and computationally screened against the receptor-binding domain (RBD) of the SARS-CoV-2 Omicron variant. As a first step, molecular docking calculations were performed for all investigated compounds. Promising compounds were subjected to molecular dynamics simulations (MD) for 200 ns, in addition to molecular mechanics Poisson-Boltzmann surface area calculations (MM/PBSA) to determine binding energy. (3) Results: MM/PBSA binding energy calculations showed that compound 14 (quercetin-3-O-ß-D-glucuronopyranoside) and compound 15 (quercetin-3-O-glucuronide 6″-O-methyl ester) exhibited strong inhibition of Omicron, with ΔGbinding of -41.0 and -32.4 kcal/mol, respectively. Finally, drug likeness evaluations based on Lipinski's rule of five also showed that the discovered compounds exhibited good oral bioavailability. (4) Conclusions: It is foreseeable that these results provide a novel intellectual contribution in light of the decreasing prevalence of SARS-CoV-2 B.1.1.529 and could be a good addition to the therapeutic protocol.


Subject(s)
COVID-19 , Euphorbia , COVID-19/drug therapy , Euphorbia/metabolism , Flavonoids/pharmacology , Glycoproteins , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
2.
RSC Adv ; 11(36): 22398-22408, 2021 Jun 21.
Article in English | MEDLINE | ID: covidwho-1815631

ABSTRACT

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan; sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds; ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets; main protease (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 Mpro that exceeded the currently used SARS-CoV-2 Mpro inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PLPro and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from -4.9 to -8.8 kcal mol-1. All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski's rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19.

3.
RSC advances ; 11(36):22398-22408, 2021.
Article in English | EuropePMC | ID: covidwho-1812594

ABSTRACT

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan;sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds;ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets;main protease (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 Mpro that exceeded the currently used SARS-CoV-2 Mpro inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PLPro and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from −4.9 to −8.8 kcal mol−1. All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski's rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19. Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads.

4.
RSC Adv ; 11(51): 32346-32357, 2021 Sep 27.
Article in English | MEDLINE | ID: covidwho-1517648

ABSTRACT

Wild plants growing in the Egyptian deserts are facing abiotic stress, which can lead to interesting & safe natural products possessing potential chemical profiles. Consequently, our study was designed to assess the phytochemical composition of the aerial parts of Limonium tubiflorum (family Plumbaginaceae) growing wild in Egypt for the first time. In addition, in silico screening and molecular dynamic simulation of all isolated phytoconstituents were run against the main protease (Mpro) and spike glycoprotein SARS-CoV-2 targets which displayed a crucial role in the replication of this virus. Our findings showed that the phytochemical investigation of 70% ethanol extract of L. tubiflorum aerial parts afforded six known flavonoids; myricetin 3-O-(2''-galloyl)-ß-d-galactopyranoside (1), myricetin 3-O-(2''-galloyl)-α-l-rhamnopyranoside (2), myricetin 3-O-(3''-galloyl)-α-l-rhamnopyranoside (3), myricetin 3-O-ß-d-galactopyranoside (5), apigenin (6), myricetin (7), along with two known phenolic acid derivatives; gallic acid (4) and ethyl gallate (8). Docking studies revealed that compounds (1) & (2) were the most effective compounds with binding energies of -17.9664 & -18.6652 kcal mol-1 against main protease and -18.9244 & -18.9272 kcal mol-1 towards spike glycoprotein receptors, respectively. The molecular dynamics simulation experiment agreed with the docking study and reported stability of compounds (1) and (2) against the selected targets which was proved by low RMSD for the tested components. Moreover, the structure-activity relationship revealed that the presence of the galloyl moiety is necessary for enhancement of the activity. Overall, the galloyl substructure of myricetin 3-O-glycoside derivatives (1 and 2) isolated from L. tubiflorum may be a possible lead for developing COVID-19 drugs. Further, in vitro and in vivo assays are recommended to support our in silico studies.

5.
RSC Adv ; 10(50): 29983-29998, 2020 Aug 10.
Article in English | MEDLINE | ID: covidwho-851319

ABSTRACT

3'-Hydroxy-4'-methoxy-chroman-7-O-ß-d-glucopyranoside 4 was first isolated from a natural source, together with three known compounds, the ferulic acid heptyl ester 1, naringenin 2, and 4,2',4'-trihydroxy-6'-methoxychalcone-4'-O-ß-d-glucopyranoside 3, which were isolated from peach [Prunus persica (L.) Batsch] fruits. These compounds were subjected to different virtual screening strategies in order to examine their activity to combat the COVID-19 outbreak. The study design composed of some major aspects: (a) docking with main protease (Mpro), (b) docking with spike protein, (c) 3D shape similarity study (Rapid Overlay Chemical Similarity-ROCS) to the clinically used drugs in COVID-19 patients, and finally, (d) the rule of five and the estimated pre-ADMT properties of the separated flavonoids. Docking study with Mpro of SARS-CoV-2 (PDB ID:6LU7, and 6Y2F) showed that compound 3, its aglycone part, and compound 4 have a strong binding mode to a protease receptor with key amino acids, especially Gln:166AA, and having a similar docking pose to co-crystalized ligands. Docking with the spike protein of SARS-CoV-2 illustrated that compounds 3 and 4 have a good binding affinity to PDB ID:6VSB through the formation of HBs with Asp:467A and Asn:422A. According to ROCS analysis, compounds 1, 3, and 4 displayed high similarities to drugs that prevent SARS-Co2 entry to the lung cells or block the inflammatory storm causing lung injury. Compounds 3 and 4 are good candidates for drug development especially because they showed predicted activity against SARS-CoV-2 through different mechanisms either by preventing genome replication or by blocking inflammatory storm that trigger lung injury. These compounds were isolated from peach fruit, and the study supports data and continues with the recommendation of peach fruits in controlling and managing COVID-19 cases.

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