Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease

Youssef, Fadia S.; Eissa, Ibrahim H.; Elkady, Hazem; Alsfouk, Aisha A.; Ashour, Mohamed L.; Hassab, Mahmoud A. El; Abou‐Seri, Sahar M.; Metwaly, Ahmed M.

doi:10.3390/ijms23136912

Cited by 45 publications

(23 citation statements)

References 127 publications

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“…A molecular docking study was performed to recognize the binding interactions by which the designed members bound to their target enzyme [ 60 , 61 , 62 , 63 ]. VEGFR-2 kinase (PDB ID: 4ASD) was utilized as a putative binding site in this study.…”

Section: Resultsmentioning

confidence: 99%

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

et al. 2022

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This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative of our previous work concerned with the development of VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast cancer (MCF-7), colorectal carcinoma (HCT116), and hepatocellular carcinoma (HepG2). The synthesized compounds were also evaluated against VEGFR-2 kinase activity. The biological testing fallouts showed that compound 8d was more potent than standard sorafenib. Such compound showed IC50 values of 3.43, 2.79, and 2.43 µM against the aforementioned cancer cell lines, respectively, compared to IC50 values of 4.21, 5.30, and 3.40 µM reported for sorafenib. Compound 8d also was found to exert exceptional VEGFR-2 inhibition activity with an IC50 value of 0.0554 μM compared to sorafenib (0.0782 μM). In addition, compound 8h revealed excellent cytotoxic effects with IC50 values of 3.53, 2.94, and 2.76 µM against experienced cell lines, respectively. Furthermore, compounds 8a and 8e were found to inhibit VEGFR-2 kinase activity with IC50 values of 0.0579 and 0.0741 μM, exceeding that of sorafenib. Compound 8d showed a significant apoptotic effect and arrested the HepG2 cells at the pre-G1 phase. In addition, it exerted a significant inhibition for TNF-α (90.54%) and of IL-6 (92.19%) compared to dexamethasone (93.15%). The molecular docking studies showed that the binding pattern of the new compounds to VEGFR-2 kinase was similar to that of sorafenib.

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Section: Resultsmentioning

confidence: 99%

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

et al. 2022

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“…ADMET profile was determined by Discovery Studio 2016 (Vélizy-Villacoublay, France) [ 36 ]. Supplementary Materials provide a thorough explanation.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

et al. 2022

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A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact with the VEGFR-2 catalytic pocket. The ability of the designed congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, to bind with the VEGFR-2 enzyme was demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established the excellent binding of compound 10 with VEGFR-2 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed the proper binding with a total exact binding energy of −38.36 Kcal/Mol. MM-GBSA studies also revealed the crucial amino acids in the binding through the free binding energy decomposition and declared the interactions variation of compound 10 inside VEGFR-2 via the Protein–Ligand Interaction Profiler (PLIP). Being new, its molecular structure was optimized by DFT. The DFT studies also confirmed the binding mode of compound 10 with the VEGFR-2. ADMET (in silico) profiling indicated the examined compound’s acceptable range of drug-likeness. The designed compound was synthesized through the condensation of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group. The in-vitro studies were consonant with the obtained in silico results as compound 10 prohibited VEGFR-2 with an IC50 value of 51 nM. Compound 10 also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC50 values of 8.25 and 6.48 μM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively.

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“…[ 19 , 20 , 21 ]. Additionally, we presented a well-designed in silico approach to select the most relevant inhibitor compound among a huge set of compounds and we applied that method to introduce several opportune anti-COVID-19 compounds from 69 isoflavonoids [ 22 ], semi-synthetic compounds [ 23 ], 310 natural antivirals [ 24 , 25 ], and 3009 FDA-approved compounds [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

The Computational Preventive Potential of the Rare Flavonoid, Patuletin, Isolated from Tagetes patula, against SARS-CoV-2

Metwaly

Alsfouk

Saleh

et al. 2022

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The rare flavonoid, patuletin, was isolated from the flowers of Tagetes patula growing in Egypt. The rarity of the isolated compound inspired us to scrutinize its preventive effect against COVID-19 utilizing a multi-step computational approach. Firstly, a structural similarity study was carried out against nine ligands of nine SARS-CoV-2 proteins. The results showed a large structural similarity between patuletin and F86, the ligand of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Then, a 3D-Flexible alignment study of patuletin and F86 verified the proposed similarity. To determine the binding opportunity, patuletin was docked against the RdRp showing a correct binding inside its active pocket with an energy of −20 kcal/mol that was comparable to that of F86 (−23 kcal/mol). Following, several MD simulations as well as MM-PBSA studies authenticated the accurate binding of patuletin in the RdRp via the correct dynamic and energetic behaviors over 100 ns. Additionally, in silico ADMET studies showed the general safety and drug-likeness of patuletin.

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Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease

Cited by 45 publications

References 127 publications

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

The Computational Preventive Potential of the Rare Flavonoid, Patuletin, Isolated from Tagetes patula, against SARS-CoV-2

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