Anticancer derivative of the natural alkaloid, theobromine, inhibiting EGFR protein: Computer-aided drug discovery approach

Eissa, Ibrahim H.; Yousef, Reda G.; Elkaeed, Eslam B.; Alsfouk, Aisha A.; Husein, Dalal Z.; Ibrahim, Ibrahim M.; Alesawy, Mohamed S; Elkady, Hazem; Metwaly, Ahmed M.

doi:10.1371/journal.pone.0282586

Cited by 11 publications

(5 citation statements)

References 56 publications

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“…MOE2014 software was operated to evaluate T‐1‐AFPB ’s binding to the VEGFR‐2 that has the PDB ID, 2OH4, and a resolution of 2.05 Å for by. [41] A comprehensive elucidation (Protein's preparation, ligands’ preparation, docking setup, validation and proceeding) is incorporated in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

A Theobromine Derivative with Anticancer Properties Targeting VEGFR‐2: Semisynthesis, in silico and in vitro Studies

Eissa,

Yousef,

Elkady

et al. 2023

ChemistryOpen

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A computer‐assisted drug design (CADD) approach was utilized to design a new acetamido‐N‐(para‐fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, (T‐1‐APFPB), following the pharmacophoric features of VEGFR‐2 inhibitors. The stability and reactivity of T‐1‐AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed T‐1‐AFPB’s potential to bind with and inhibit VEGFR‐2. The precise binding of T‐1‐AFPB against VEGFR‐2 with optimal energy was further confirmed through several molecular dynamics (MD) simulations, PLIP, MM‐GBSA, and PCA studies. Then, T‐1‐AFPB (4‐(2‐(3,7‐Dimethyl‐2,6‐dioxo‐2,3,6,7‐tetrahydro‐1H‐purin‐1‐yl)acetamido)‐N‐(4‐fluorophenyl)benzamide) was semi‐synthesized and the in vitro assays showed its potential to inhibit VEGFR‐2 with an IC50 value of 69 nM (sorafenib's IC50 was 56 nM) and to inhibit the growth of HepG2 and MCF‐7 cancer cell lines with IC50 values of 2.24±0.02 and 3.26±0.02 μM, respectively. Moreover, T‐1‐AFPB displayed very high selectivity indices against normal Vero cell lines. Furthermore, T‐1‐AFPB induced early (from 0.72 to 19.12) and late (from 0.13 to 6.37) apoptosis in HepG2 cell lines. In conclusion, the combined computational and experimental approaches demonstrated the efficacy and safety of T‐1‐APFPB providing it as a promising lead VEGFR‐2 inhibitor for further development aiming at cancer therapy.

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Section: Methodsmentioning

confidence: 99%

A Theobromine Derivative with Anticancer Properties Targeting VEGFR‐2: Semisynthesis, in silico and in vitro Studies

Eissa,

Yousef,

Elkady

et al. 2023

ChemistryOpen

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“…These served dual purposes as both miraculous drinks and liquid medicines due to their intoxicating and mind-Deltos • Issue 51 • June 2023 invigorates the body and reduces the risk of cancer and neurodegenerative diseases, such as cardiovascular diseases and Alzheimer's [43][44] . Theobromine has demonstrated promising anti-cancer activity by inhibiting lung cancer angiogenesis 45 , and it could potentially be utilised in meal replacement products 46 . Moreover, theobromine helps lower blood pressure, improve blood flow [47][48] , and enhance cognition and mood 49 .…”

Section: Discussionmentioning

confidence: 99%

The medical use of Málaka wine and cola nuts in late 19th/early 20th century Greece

Tsoucalas,

Vladimiros

2024

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The lands of Malaka in Spain have been renowned for their wine since the 8th century BC. Malaka wine gained popularity among merchants and consumers since the 17th century, becoming one of Europe’s favourites. The seeds (nuts) of the African Cola acuminata trees had been used in daily life as an invigorating and stimulating chewing or eating delicacy. In the late 19th century, Stamatios Krinos, who had opened one of the first (or the first) pharmacies in Athens in 1836, and his son Athanasios, produced an Elixir named Krinos Cola Wine to treat neurasthenia, chlorosis, anaemia, indigestion, gastralgia, chronic diarrhoea, cardiopathies, weakness and infertility. The properties of both the wine and the nuts, along with the chemical compounds of cola, were already known by the mid-19th century and the Krinos family took advantage of this knowledge to introduce a novel herbal drug (cola seeds) to the Hellenic pharmacopeia. The properties attributed to the Krinos elixir are de novo and in depth validated today by a series of modern medical studies. The fact that cola was not included as a therapeutic agent in the Hellenic textbooks of pharmacology of that era suggests that Krinos made an innovative addition to the timelessly popular Hellenic herbal medicine and pharmacopeia.

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“…This article reports on the ongoing research of our team to discover potential anticancer agents that target EGFR protein. 45,[48][49][50][51][52] The focus of this paper is to introduce a newly synthesized compound, T-1-DOCA, which exhibits promising in silico and in vitro anticancer properties. This novel compound was specifically designed and synthesized to target EGFR protein and represents a potential lead compound in the development of new anticancer agents.…”

Section: Rationalementioning

confidence: 99%

Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer

Eissa,

Yousef,

Elkaeed

et al. 2023

Evol Bioinform Online

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The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (T-1-DOCA). Firstly, T-1-DOCA’s total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of T-1-DOCA against wild and mutant EGFR proteins. T-1-DOCA’s correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, T-1-DOCA showed noticeable efficacy compared to erlotinib by suppressing EGFRWT and EGFRT790M with IC50 values of 56.94 and 269.01 nM, respectively. T-1-DOCA inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC50 values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of T-1-DOCA were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, T-1-DOCA, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that T-1-DOCA is a promising candidate for further development as an anti-cancer drug.

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Anticancer derivative of the natural alkaloid, theobromine, inhibiting EGFR protein: Computer-aided drug discovery approach

Cited by 11 publications

References 56 publications

A Theobromine Derivative with Anticancer Properties Targeting VEGFR‐2: Semisynthesis, in silico and in vitro Studies

A Theobromine Derivative with Anticancer Properties Targeting VEGFR‐2: Semisynthesis, in silico and in vitro Studies

The medical use of Málaka wine and cola nuts in late 19th/early 20th century Greece

Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer

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