Isolation and In Silico Inhibitory Potential against SARS-CoV-2 RNA Polymerase of the Rare Kaempferol 3-O-(6″-O-acetyl)-Glucoside from Calligonum tetrapterum

Suleimen, E. M.; Jose, Rani A.; Mamytbekova, G. K.; Suleimen, R. N.; Ishmuratova, Margarita; Dehaen, Wim; Alsfouk, Bshra A.; Eissa, Ibrahim H.; Metwaly, Ahmed M.

doi:10.3390/plants11152072

Cited by 16 publications

(9 citation statements)

References 65 publications

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“…Discovery studio 4.0 85 was used for the selected four metabolites (see method part in Supplementary data).…”

Section: Methodsmentioning

confidence: 99%

Computer-aided drug discovery of natural antiviral metabolites as potential SARS-CoV-2 helicase inhibitors

Elkaeed,

Eissa,

Saleh

et al. 2024

Journal of Chemical Research

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In our quest to discover effective inhibitors against severe acute respiratory syndrome coronavirus 2 helicase, a diverse set of more than 300 naturally occurring antiviral metabolites was investigated. Employing advanced computational techniques, we initiated the selection process by analyzing and comparing the co-crystallized ligand (VXG) of the severe acute respiratory syndrome coronavirus 2 helicase protein (PDB ID: 5RMM) to identify compounds with structurally similar features and potential for comparable binding. Through structural similarity and pharmacophore research, 13 compounds that shared important characteristics with VXG were pinpointed. Subsequently, these candidates were subjected to molecular docking to identify seven compounds that demonstrated favorable energy profiles and accurate binding to the severe acute respiratory syndrome coronavirus 2 helicase. Among these, mycophenolic acid emerged as the most promising candidate. To ensure the safety and viability of the selected compounds, we conducted ADMET tests, which confirmed the favorable characteristics of mycophenolic acid, and the safety of atropine and plumbagin. Building on these results, we performed additional analyses on mycophenolic acid, including various molecular dynamics simulations. These investigations demonstrated that mycophenolic acid exhibited optimal binding to the severe acute respiratory syndrome coronavirus 2 helicase, maintaining flawless dynamics throughout the simulations. Furthermore, the Molecular Mechanics Poisson–Boltzmann Surface Area tests provided strong evidence that mycophenolic acid successfully formed a stable connection with the severe acute respiratory syndrome coronavirus 2 helicase, with a calculated free energy value of −294 kJ mol−1. These encouraging findings provide a solid foundation for further research, including in vitro and in vivo studies, on the three identified compounds. The potential efficacy of these compounds as treatment options for coronavirus-19 warrants further exploration and may hold significant promise in the ongoing fight against the pandemic.

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“…Discovery studio 4.0 85 was used for the selected four metabolites (see method part in Supplementary data).…”

Section: Methodsmentioning

confidence: 99%

Computer-aided drug discovery of natural antiviral metabolites as potential SARS-CoV-2 helicase inhibitors

Elkaeed,

Eissa,

Saleh

et al. 2024

Journal of Chemical Research

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“…The accuracy of the protocol was confirmed by comparing the redocked VXG RMSD with the co-crystallized reference. For tested compounds, 30 docked solutions were generated, and Discovery Studio 4.0 visualized and analyzed results against the VXG reference 80 as elucidated in greater detail within the Supplementary Data section.…”

Section: Methodsmentioning

confidence: 99%

Computer-Assisted Drug Discovery of Potential African Anti-SARS-CoV-2 Natural Products Targeting the Helicase Protein

Metwaly,

Alesawy,

Alsfouk

et al. 2024

Natural Product Communications

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Objectives: In our continuous efforts to combat COVID-19, our objective was to conduct a comprehensive computer-aided drug design study utilizing 4924 African natural metabolites sourced from diverse databases across various African regions from 1962 to 2019. The primary goal was to target the SARS-CoV-2 helicase, a crucial enzyme in viral replication. Methods: We employed structural fingerprint and molecular similarity studies with VXG, the co-crystallized ligand, as a reference. Subsequently, docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were conducted. Results: The structural fingerprint analysis identified 200 structurally similar compounds, then the molecular similarity studies selected 40 compounds. Among them, 15 metabolites with low free energies, favorable binding modes, and promising ADMET properties were identified. Four compounds were excluded according to the toxicity studies. Compound 1552, 1-(( S)-2,3-dihydro-2-(( R)-1-hydroxypropan-2-yl)benzofuran-5-yl)ethenone, exhibited the most favorable docking results. Molecular dynamics simulations conclusively demonstrated its stable binding to the SARS-CoV-2 helicase, characterized by low energy and optimal dynamics. Conclusion: The findings suggest promising avenues for potential COVID-19 cures, encouraging further exploration through in vitro and in vivo studies of the identified compounds, particularly compound 1552.

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“…Docking studies were operated for T-1-PMPA against EGFR WT (wild form) and EGFR T790M (mutant form) by MOE2014 software. 75 The Supporting Section of this document offers detailed representations and additional elaborations.…”

Section: Methodsmentioning

confidence: 99%

New Theobromine Apoptotic Analogue with Anticancer Potential Targeting the EGFR Protein: Computational and In Vitro Studies

Eissa,

Yousef,

Elkaeed

et al. 2024

ACS Omega

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Aim: The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics of existing EGFR inhibitors as a foundation. Method: The study began with the natural alkaloid theobromine and developed a new semisynthetic derivative (T-1-PMPA). Computational ADMET assessments were conducted first to evaluate its anticipated safety and general drug-likeness. Deep density functional theory (DFT) computations were initially performed to validate the three-dimensional (3D) structure and reactivity of T-1-PMPA. Molecular docking against the EGFR proteins was conducted to investigate T-1-PMPA’s binding affinity and inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along with MM-GPSA, PLIP, and principal component analysis of trajectories (PCAT) experiments were employed to verify the binding and inhibitory properties of T-1-PMPA. Afterward, T-1-PMPA was semisynthesized to validate the proposed design and in silico findings through several in vitro examinations. Results: DFT studies indicated T-1-PMPA’s reactivity using electrostatic potential, global reactive indices, and total density of states. Molecular docking, MD simulations, MM-GPSA, PLIP, and ED suggested the binding and inhibitory properties of T-1-PMPA against the EGFR protein. The in silico ADMET predicted T-1-PMPA’s safety and general drug-likeness. In vitro experiments demonstrated that T-1-PMPA effectively inhibited EGFRWT and EGFR790m, with IC50 values of 86 and 561 nM, respectively, compared to Erlotinib (31 and 456 nM). T-1-PMPA also showed significant suppression of the proliferation of HepG2 and MCF7 malignant cell lines, with IC50 values of 3.51 and 4.13 μM, respectively. The selectivity indices against the two cancer cell lines indicated the overall safety of T-1-PMPA. Flow cytometry confirmed the apoptotic effects of T-1-PMPA by increasing the total percentage of apoptosis to 42% compared to 31, and 3% in Erlotinib-treated and control cells, respectively. The qRT-PCR analysis further supported the apoptotic effects by revealing significant increases in the levels of Casp3 and Casp9. Additionally, T-1-PMPA controlled the levels of TNFα and IL2 by 74 and 50%, comparing Erlotinib’s values (84 and 74%), respectively. Conclusion: In conclusion, our study’s findings suggest the potential of T-1-PMPA as a promising apoptotic anticancer lead compound targeting the EGFR.

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Isolation and In Silico Inhibitory Potential against SARS-CoV-2 RNA Polymerase of the Rare Kaempferol 3-O-(6″-O-acetyl)-Glucoside from Calligonum tetrapterum

Cited by 16 publications

References 65 publications

Computer-aided drug discovery of natural antiviral metabolites as potential SARS-CoV-2 helicase inhibitors

Computer-aided drug discovery of natural antiviral metabolites as potential SARS-CoV-2 helicase inhibitors

Computer-Assisted Drug Discovery of Potential African Anti-SARS-CoV-2 Natural Products Targeting the Helicase Protein

New Theobromine Apoptotic Analogue with Anticancer Potential Targeting the EGFR Protein: Computational and In Vitro Studies

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