A Multistage In Silico Study of Natural Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Elkaeed, Eslam B.; Eissa, Ibrahim H.; Elkady, Hazem; Abdelalim, Ahmed; Alqaisi, Ahmad M.; Alsfouk, Aisha A.; Elwan, Alaa; Metwaly, Ahmed M.

doi:10.3390/ijms23158407

Cited by 43 publications

(16 citation statements)

References 109 publications

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“…CHARMM-GUI web server and GROMACS 2021 were utilized as an MD engine [ 49 , 50 ]. An extensive explanation is presented in the Supplementary Materials .…”

Section: Methodsmentioning

confidence: 99%

A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

Eissa

Yousef

Elkady

et al. 2023

Life

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A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is a (para-chloro)acetamide derivative of the alkaloid, theobromine, (T-1-PCPA). At first, we started with deep density functional theory (DFT) calculations for T-1-PCPA to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for T-1-PCPA. Secondly, the affinity of T-1-PCPA to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFRWT and EGFRT790M, Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of T-1-PCPA have been investigated and its safety and the general drug-likeness predicted. Accordingly, T-1-PCPA was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly, T-1-PCPA inhibited in vitro EGFRWT with an IC50 value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally, T-1-PCPA inhibited the growth of A549 and HCT-116 malignant cell lines with IC50 values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC50 values of 6.73 and 16.35 µM, respectively.

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“…CHARMM-GUI web server and GROMACS 2021 were utilized as an MD engine [ 49 , 50 ]. An extensive explanation is presented in the Supplementary Materials .…”

Section: Methodsmentioning

confidence: 99%

A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

Eissa

Yousef

Elkady

et al. 2023

Life

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“…ADMET descriptors were determined using Discovery studio 4.0 as according to the reported method 42–45 (ESI†).…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis, anticancer evaluation, and in silico ADMET analysis of novel thalidomide analogs as promising immunomodulatory agents

et al. 2023

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“…Molecular docking as carried out against VEGFR-2 (ID: 4ASD) using the Molecular Operating Environment (MOE) 2014 software [ 72 , 73 , 74 , 75 , 76 ]. The Supplementary data provides further detailed information about the study.…”

Section: Methodsmentioning

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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A Multistage In Silico Study of Natural Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Cited by 43 publications

References 109 publications

A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

Design, synthesis, anticancer evaluation, and in silico ADMET analysis of novel thalidomide analogs as promising immunomodulatory agents

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

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