Identification of natural flavonoids as novel EGFR inhibitors using DFT, molecular docking, and molecular dynamics

Sepay, Nayim; Mondal, Rina; Al-Muhanna, Muhanna K.; Saha, Debajyoti

doi:10.1039/d2nj00389a

Cited by 25 publications

(18 citation statements)

References 53 publications

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“…Therefore, the inhibitory activity of PD13/EGFRs was induced by the two key residues, which are M793 and S797, at the hinge region. The main EGFR residues (L718, M793, and S797) evidenced crucial binding via hydrogen bonds, which is similar to other reported EGFR tyrosine kinases such as tupichinol E [46], quinazoline [47], and 9-heterocyclyl substituted 9H-purine derivatives [48].…”

Section: Protein-ligand Hydrogen Bondingsupporting

confidence: 85%

Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study

et al. 2023

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Targeting L858R/T790M and L858R/T790M/C797S mutant EGFR is a critical challenge in developing EGFR tyrosine kinase inhibitors to overcome drug resistance in non-small cell lung cancer (NSCLC). The discovery of next-generation EGFR tyrosine kinase inhibitors (TKIs) is therefore necessary. To this end, a series of furopyridine derivatives were evaluated for their EGFR-based inhibition and antiproliferative activities using computational and biological approaches. We found that several compounds derived from virtual screening based on a molecular docking and solvated interaction energy (SIE) method showed the potential to suppress wild-type and mutant EGFR. The most promising PD13 displayed strong inhibitory activity against wild-type (IC50 of 11.64 ± 1.30 nM), L858R/T790M (IC50 of 10.51 ± 0.71 nM), which are more significant than known drugs. In addition, PD13 revealed a potent cytotoxic effect on A549 and H1975 cell lines with IC50 values of 18.09 ± 1.57 and 33.87 ± 0.86 µM, respectively. The 500-ns MD simulations indicated that PD13 formed a hydrogen bond with Met793 at the hinge region, thus creating excellent EGFR inhibitory activity. Moreover, the binding of PD13 in the hinge region of EGFR was the major determining factor in stabilizing the interactions via hydrogen bonds and van der Waals (vdW). Altogether, PD13 is a promising novel EGFR inhibitor that could be further clinically developed as fourth-generation EGFR-TKIs.

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Section: Protein-ligand Hydrogen Bondingsupporting

confidence: 85%

Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study

et al. 2023

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“…In our study, the interactions between ligands and amino acids were defined as follows: hydrogen bond: 3.40 Å; D–H–A angle: 90–180°; CH–π interaction: 5.0 Å; angle: 40°; π–π interaction: 6.0 Å; angle: 50°; van der Waals interaction: 5.5 Å. 47…”

Section: Methodsmentioning

confidence: 99%

Identification of 4-acrylamido-N-(pyridazin-3-yl)benzamide as anti-COVID-19 compound: a DFTB, molecular docking, and molecular dynamics study

Sepay¹,

Chakrabarti²,

Afzal

et al. 2022

RSC Adv.

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“…In the past few years, there have been several reports on the use of molecular docking to predict the binding affinity and interaction between some of the flavonoids and specific protein targets. However, these studies involved only one or a few flavonoids (e.g., apigenin, luteolin genistein, or quercetin) with a few targeted proteins [48][49][50][51][52][53][54][55][56]. In contrast, in our study, we compared the binding energy values and interactions of apigenin with different 24 receptors (proteins) to those of 15 flavonoids belonging to flavones, isoflavones, and flavonols (Table 1).…”

Section: Introductionmentioning

confidence: 94%

In silico comparison of apigenin and related compounds with diverse pharmacological activities using AutoDock 4.2.6

Peanlikhit,

Aryal,

Welsh

et al. 2024

Preprint

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In recent years, molecular docking has been used to predict the binding affinity and interaction between flavonoids (ligands) and specific protein targets (receptors). However, existing studies have focused on a limited number of flavonoids with a small number of targeted proteins. In this study, on the other hand, we used the AutoDock 4.2.6 molecular docking software to compare the binding energy values and interactions of apigenin and 15 flavonoids with 24 different proteins known to be associated with oxidative stress, inflammation, carcinogenesis, and bacterial infections. This comparison will be important for the development of flavonoid-based drugs, allowing for the optimization of flavonoid drugs to better interact with their target proteins alone or in combination with conventional drugs. We used three-dimensional crystal structures of the receptors to identify the amino acids in the active site for docking purposes. Our goal was to identify potential inhibitors of these proteins and understand the structural configurations of flavonoids that affect their binding energy (binding affinity or inhibitory effects). We found that apigenin was a highly effective inhibitor for all tested proteins, with the highest binding energy of -8.21 kcal/mol with p38 mitogen-activated protein kinases and the lowest binding energy of -5.34 kcal/mol with cyclin-dependent kinase 4. In fact, apigenin and most of the tested flavonoids were better inhibitors for xanthine oxidase or DNA methyltransferase than known inhibitors. Our results also suggest that apigenin and selected flavonoids could be used to inhibit the oncogenic activity of KRAS mutations at codon 12 (i.e., G12C, G12D, and G12V) frequently found in solid tumors since they possess high binding energies with these mutated proteins. This finding offers an advantage over targeted therapy drugs that focus on specific KRAS mutations. Furthermore, most flavonoids have good safety profiles, so our resulting data are crucial for developing flavonoid-based drugs and present new insights into developing effective treatments that can attenuate the resistance and side effects of chemotherapy.

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Identification of natural flavonoids as novel EGFR inhibitors using DFT, molecular docking, and molecular dynamics

Abstract: Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that causes different types of cancer on its overexpression or mutation and rearrangement or amplification of the EGFR gene. Inhibition...

Cited by 25 publications

References 53 publications

Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study

Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study

Identification of 4-acrylamido-N-(pyridazin-3-yl)benzamide as anti-COVID-19 compound: a DFTB, molecular docking, and molecular dynamics study

In silico comparison of apigenin and related compounds with diverse pharmacological activities using AutoDock 4.2.6

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