Investigating the structure-activity relationship of marine polycyclic batzelladine alkaloids as promising inhibitors for SARS-CoV-2 main protease (Mpro)

Elgohary, Alaa M.; Elfiky, Abdo A.; Pereira, Florbela; El-Aziz, Tarek Mohamed Abd; Sobeh, Mansour; Arafa, Reem K.; El-Demerdash, Amr

doi:10.1016/j.compbiomed.2022.105738

Cited by 8 publications

(3 citation statements)

References 83 publications

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“…Elgohary et al targeted the main protease of SARS-CoV 2 virus with 15 batzelladine marine alkaloids. They started their approach by performing docking followed by MD simulation and SAR 48 . Kumar et al have performed high throughput screening of an in-house database against NSP15 followed by MD simulation for the high-ranked compounds.…”

Section: Discussionmentioning

confidence: 99%

Targeting SARS-CoV-2 endoribonuclease: a structure-based virtual screening supported by in vitro analysis

Ibrahim

Elfiky

Fathy

et al. 2022

Sci Rep

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Researchers are focused on discovering compounds that can interfere with the COVID-19 life cycle. One of the important non-structural proteins is endoribonuclease since it is responsible for processing viral RNA to evade detection of the host defense system. This work investigates a hierarchical structure-based virtual screening approach targeting NSP15. Different filtering approaches to predict the interactions of the compounds have been included in this study. Using a deep learning technique, we screened 823,821 compounds from five different databases (ZINC15, NCI, Drug Bank, Maybridge, and NCI Diversity set III). Subsequently, two docking protocols (extra precision and induced fit) were used to assess the binding affinity of the compounds, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy. Interestingly, one compound (ZINC000104379474) from the ZINC15 database has been found to have a good binding affinity of − 7.68 kcal/Mol. The VERO-E6 cell line was used to investigate its therapeutic effect in vitro. Half-maximal cytotoxic concentration and Inhibitory concentration 50 were determined to be 0.9 mg/ml and 0.01 mg/ml, respectively; therefore, the selectivity index is 90. In conclusion, ZINC000104379474 was shown to be a good hit for targeting the virus that needs further investigations in vivo to be a drug candidate.

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Section: Discussionmentioning

confidence: 99%

Targeting SARS-CoV-2 endoribonuclease: a structure-based virtual screening supported by in vitro analysis

Ibrahim

Elfiky

Fathy

et al. 2022

Sci Rep

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“…O6K is a covalently bound ligand, but we redock it to the solved structure in a non-bonded fashion, and it gives a root-mean-square difference of 0.966 Å. Additionally, the peptidyl Michael acceptor, N3, found in the solved structure of Mpro (PDB ID: 6LU7) is also used as a positive control for comparison [ 30 ]. The M pro dimer was subjected to molecular dynamics simulation (MDS) which ran for 80 nanoseconds, as reported [ 41 ] before the docking study. The MDS was conducted on the WEBGRO macromolecular simulation utilizing GROningen MAchine for Chemical Simulations (GROMACS) software and CHARMM27 force field [ 42 , 43 ].…”

Section: Computational Analysismentioning

confidence: 99%

Synthesis and In Silico Study of Some New bis-[1,3,4]thiadiazolimines and bis-Thiazolimines as Potential Inhibitors for SARS-CoV-2 Main Protease

Gomha

Riyadh

Abdellattif

et al. 2022

CIMB

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A novel series of bis-[1,3,4]thiadiazolimines, and bis-thiazolimines, with alkyl linker, were synthesized through general routes from cyclization of 1,1′-(hexane-1,6-diyl)bis(3-phenylthiourea) and hydrazonoyl halides or α-haloketones, respectively. Docking studies were applied to test the binding affinity of the synthesized products against the Mpro of SARS-CoV-2. The best compound, 5h, has average binding energy (−7.50 ± 0.58 kcal/mol) better than that of the positive controls O6K and N3 (−7.36 ± 0.34 and −6.36 ± 0.31 kcal/mol). Additionally, the docking poses (H-bonds and hydrophobic contacts) of the tested compounds against the Mpro using the PLIP web server were analyzed.

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“…The current study uses molecular modeling and molecular dynamics simulations to examine the potential therapeutic uses of major protease inhibitors for SARS-CoV-2 (7). The investigation of ligand-protein interactions at the molecular level using molecular modeling is an effective method for learning more about the structure-activity relationships of ligands (8,9). The kinetics of ligand-2 protein interactions are investigated using molecular dynamics simulations, which can reveal details about the stability of the protein-ligand complex and the binding free energy (10).…”

Section: Introductionmentioning

confidence: 99%

A Molecular Modeling and Molecular Dynamics Simulations Investigation of the Potential Therapeutic Applications of Main Protease Inhibitors for SARS-CoV-2

Mushebenge,

Ugbaja,

Mbatha

et al. 2023

Preprint

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A major public health emergency has been created by the COVID-19 pandemic, which is brought on by the SARS-CoV-2 virus. Due to its crucial function in viral replication, the primary protease (Mpro) of the virus is a prime target for therapeutic research. In this study, we used molecular modeling and molecular dynamics simulations to examine the potential therapeutic uses of Mpro inhibitors for the treatment of COVID-19. Using induced fit docking and molecular dynamics simulations, we confirmed the top compounds after screening a library of compounds for their ability to bind to Mpro. Simulation interaction diagrams were used to investigate protein-ligand interactions, and MM-GBSA was used to determine binding energies. The Swiss ADME server was used to predict ADME properties. According to our findings, numerous substances are strong COVID-19 medication candidates since they have excellent ADME features and high binding affinities. This work serves as a foundation for additional experimental research and drug development initiatives aimed at Mpro.

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Investigating the structure-activity relationship of marine polycyclic batzelladine alkaloids as promising inhibitors for SARS-CoV-2 main protease (Mpro)

Cited by 8 publications

References 83 publications

Targeting SARS-CoV-2 endoribonuclease: a structure-based virtual screening supported by in vitro analysis

Targeting SARS-CoV-2 endoribonuclease: a structure-based virtual screening supported by in vitro analysis

Synthesis and In Silico Study of Some New bis-[1,3,4]thiadiazolimines and bis-Thiazolimines as Potential Inhibitors for SARS-CoV-2 Main Protease

A Molecular Modeling and Molecular Dynamics Simulations Investigation of the Potential Therapeutic Applications of Main Protease Inhibitors for SARS-CoV-2

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