In Silico Mining of Terpenes from Red-Sea Invertebrates for SARS-CoV-2 Main Protease (Mpro) Inhibitors

Ibrahim, Mahmoud A. A.; Abdelrahman, Alaa H. M.; Mohamed, Tarik A.; Atia, Mohamed A. M.; Abdeljawaad, Khlood A. A.; Elkady, Eman M.; Moustafa, Mahmoud; Alrumaihi, Faris; Allemailem, Khaled S.; El‐Seedi, Hesham R.; Paré, Paul W.; Efferth, Thomas; Hegazy, Mohamed‐Elamir F.

doi:10.3390/molecules26072082

Cited by 42 publications

(28 citation statements)

References 56 publications

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“…Erylosides B, a terpene marine natural product, demonstrated preferential MM-GBSA binding energy with M pro over 100 ns MD simulation (calc. −51.9 kcal/mol) [ 8 ]. Comparing the MM-GBSA binding affinity of 340 to the earlier identified compounds robustly unveiled its competing binding affinity as a prospective M pro inhibitor.…”

Section: Resultsmentioning

confidence: 99%

“…Drug repurposing can be achieved by conducting systematic drug-drug target interaction and drug-drug interaction analyses [ 6 ]. Another approach is to examine a class or source of natural products with established biological activity; indeed, several in silico studies have been developed to screen for SARS-CoV-2 inhibitors as prospective anti-COVID-19 drug candidates [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Natural products play a pivotal role in designing novel and efficient treatments to conquer the current COVID-19 epidemic.…”

Section: Introductionmentioning

confidence: 99%

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Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition

et al. 2021

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The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < −33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of −43.8 and −34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition

et al. 2021

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“…Ethanol is processed in the body to release superoxide anion and hydroperoxy free radicals. The oxygen-resultant free radicals were found to be involved in the stomach ulcer mechanism [40]. Several mechanisms are implicated in ulcer origin in many models.…”

Section: Discussionmentioning

confidence: 99%

“…The PDB file for the H + /K + -ATPase α chain was downloaded from the SwissProt database (https://swissmodel.expasy.org, accessed on 12 January 2021) (ID: P20648). A previous published protocol for molecular docking of natural metabolites to target proteins was followed [37][38][39][40]. Docking parameters were set to 250 runs and 25,000,000 energy evaluations for each cycle.…”

Section: Molecular Dockingmentioning

confidence: 99%

Gastroprotection against Rat Ulcers by Nephthea Sterol Derivative

et al. 2021

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Different species belonging to the genus Nephthea (Acyonaceae) are a rich resource for bioactive secondary metabolites. The literature reveals that the gastroprotective effects of marine secondary metabolites have not been comprehensively studied in vivo. Hence, the present investigation aimed to examine and determine the anti-ulcer activity of 4α,24-dimethyl-5α-cholest-8β,18-dihydroxy,22E-en-3β-ol (ST-1) isolated from samples of a Nephthea species. This in vivo study was supported by in silico molecular docking and protein–protein interaction techniques. Oral administration of ST-1 reduced rat stomach ulcers with a concurrent increase in gastric mucosa. Molecular docking calculations against the H+/K+-ATPase transporter showed a higher binding affinity of ST-1, with a docking score value of −9.9 kcal/mol and a pKi value of 59.7 nM, compared to ranitidine (a commercial proton pump inhibitor, which gave values of −6.2 kcal/mol and 27.9 µM, respectively). The combined PEA-reactome analysis results revealed promising evidence of ST-1 potency as an anti-ulcer compound through significant modulation of the gene set controlling the PI3K signaling pathway, which subsequently plays a crucial role in signaling regarding epithelialization and tissue regeneration, tissue repairing and tissue remodeling. These results indicate a probable protective role for ST-1 against ethanol-induced gastric ulcers.

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“…In seeking potential natural products to combat COVID-19 disease, the molecular docking technique was applied to portend the binding modes and affinities of 40 propolis derivatives towards five viral targets and one human target, namely 3CL pro , RNA-dependent RNA polymerase (RdRp), papain-like protease (PLpro), receptor-binding domain (RBD) of the spike protein (S-protein), helicase (NSP13), and human angiotensin-converting enzyme 2 (ACE2). The technical details of the employed molecular docking calculations are described in References [129][130][131][132][133][134][135][136]. In brief, the crystal structures of SARS-CoV-2 3CL pro (PDB code: 6LU7) [137], RdRp (PDB code: 6M71) [138], PL pro (PDB code: 6W9C) [139], RBD (PDB code: 6M0J) [140], and NSP13 (PDB code: 5RMM) [141] were opted for as templates for all molecular docking calculations.…”

Section: In Silico Drug Discoverymentioning

confidence: 99%

Anti-Viral and Immunomodulatory Properties of Propolis: Chemical Diversity, Pharmacological Properties, Preclinical and Clinical Applications, and In Silico Potential against SARS-CoV-2

Yosri

El-Wahed

Ghonaim

et al. 2021

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Propolis, a resin produced by honeybees, has long been used as a dietary supplement and folk remedy, and more recent preclinical investigations have demonstrated a large spectrum of potential therapeutic bioactivities, including antioxidant, antibacterial, anti-inflammatory, neuroprotective, immunomodulatory, anticancer, and antiviral properties. As an antiviral agent, propolis and various constituents have shown promising preclinical efficacy against adenoviruses, influenza viruses, respiratory tract viruses, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over 300 chemical components have been identified in propolis, including terpenes, flavonoids, and phenolic acids, with the specific constituent profile varying widely according to geographic origin and regional flora. Propolis and its constituents have demonstrated potential efficacy against SARS-CoV-2 by modulating multiple pathogenic and antiviral pathways. Molecular docking studies have demonstrated high binding affinities of propolis derivatives to multiple SARS-CoV-2 proteins, including 3C-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), the receptor-binding domain (RBD) of the spike protein (S-protein), and helicase (NSP13), as well as to the viral target angiotensin-converting enzyme 2 (ACE2). Among these compounds, retusapurpurin A has shown high affinity to 3CLpro (ΔG = −9.4 kcal/mol), RdRp (−7.5), RBD (−7.2), NSP13 (−9.4), and ACE2 (−10.4) and potent inhibition of viral entry by forming hydrogen bonds with amino acid residues within viral and human target proteins. In addition, propolis-derived baccharin demonstrated even higher binding affinity towards PLpro (−8.2 kcal/mol). Measures of drug-likeness parameters, including metabolism, distribution, absorption, excretion, and toxicity (ADMET) characteristics, also support the potential of propolis as an effective agent to combat COVID-19.

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In Silico Mining of Terpenes from Red-Sea Invertebrates for SARS-CoV-2 Main Protease (Mpro) Inhibitors

Cited by 42 publications

References 56 publications

Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition

Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition

Gastroprotection against Rat Ulcers by Nephthea Sterol Derivative

Anti-Viral and Immunomodulatory Properties of Propolis: Chemical Diversity, Pharmacological Properties, Preclinical and Clinical Applications, and In Silico Potential against SARS-CoV-2

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