Potential tripeptides against the tyrosine kinase domain of human epidermal growth factor receptor (HER) 2 through computational and kinase assay approaches

Seetaha, Supaphorn; Boonyarit, Bundit; Tongsima, Sissades; Songtawee, Napat; Choowongkomon, Kiattawee

doi:10.1016/j.jmgm.2020.107564

Cited by 4 publications

(5 citation statements)

References 39 publications

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“…ΔG solv = ΔG polar + ΔG nonpolar determined the higher IC 50 values at the mM range of tripeptides WWW and FYW against HER2-TK, a homolog of EGFR-TK (Seetaha et al, 2020). The IC 50 value of the drug lapatinib against HER2-TK was at the same level as that erlotinib exerted on EGFR-TK in this study.…”

Section: Inhibitory Activity and Cytotoxicity Of Tripeptidessupporting

confidence: 54%

“…Those peptides also have a potential to inhibit the proliferation and anti-apoptotic effect of the NSCLC cell line (Kuroda et al, 2013). We have recently utilized the computational drug design approach combined with in vitro experiments to identify the tripeptides that have a promising inhibitory activity against HER2-TK (Seetaha et al, 2020). In this study with the same proof-of-concept, we selected five tripeptides with high scores from the molecular docking-based virtual screening of eight thousand tripeptides for in vitro experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Small peptides are a class of biomolecules that have come to be used to overcome multiple obstacles confronting those chemicalbased inhibitors (Abe et al, 2008;Kuroda et al, 2013). Our previous work with molecular docking-based virtual screening followed by molecular dynamic simulations on tripeptides against the human epithelial growth factor receptor 2 tyrosine kinase domain (HER2-TK) demonstrated that the tripeptides, WWW and FYW, elicited a promising capacity similar to lapatinib in terms of binding avidity (Seetaha et al, 2020). Herein, we used computational analysis combined with in vitro assays to identify a tripeptide against EGFR-TK according to the structure-based drug design strategy.…”

Section: Introductionmentioning

confidence: 99%

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Identification of tripeptides against tyrosine kinase domain of EGFR for lung cancer cell inhibition by in silico and in vitro studies

et al. 2021

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Epidermal growth factor receptor tyrosine kinase domain (EGFR-TK) has been one of the prominent targets for therapeutics of several human cancers, in particular non-small cell lung cancer. Although several small chemical compounds targeting EGFR-TK have been approved by FDA for treatment of such a cancer, the discovery of a new class of EGFR-TK inhibitors, for example, small peptides, is still desired. In this study, using molecular docking-based virtual screening, we selected five small peptides with high docking scores from eight thousand peptides as candidate compounds against EGFR-TK. Among five, the tripeptide WFF had the most potency to suppress the survival of non-small cell lung cancer cells but had the least toxicity to human liver cancer cells. Our in vitro kinase assays showed that WFF exhibited much lower inhibitory activity against purified EGFR-TK than the drug erlotinib (i.e., IC 50 values of ≈ 0.62 μM vs ≈ 7.57 nM, respectively). The relative free binding energies estimated from molecular dynamic simulations were consistent with the in vitro experiments in which the WFF bound had a lower affinity than erlotinib bound to EGFR-TK (i.e., ΔG bind values of −20.3 kJ/mol vs ≈ −126.8 kJ/mol, respectively). In addition, the simulation analyses demonstrated the difference in EGFR binding preference between the drug and tripeptide in which erlotinib was stably bound in the ATP-binding pocket for 4-anilinoquinazoline class of inhibitors, while WFF moved out of that pocket to interact with polar amino acid residues on the αC-helix, activation loop,

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Section: Inhibitory Activity and Cytotoxicity Of Tripeptidessupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of tripeptides against tyrosine kinase domain of EGFR for lung cancer cell inhibition by in silico and in vitro studies

et al. 2021

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“…The inhibitions of kinase toward JAK2/3 (Sigma-Aldrich: SRP0171, SRP0173) of screened compounds were measured by using the ADP-Glo Kinase Assay Kit (Promega). , The reaction consists of 2.5 ng/μL of JAK2/3, screened compounds at 1 μM, 5 μM ATP and 2 ng/μLpoly(glu·tyr) in a buffer (40 mM Tris–HCI pH 7.5, 20 mM MgCl 2 , and 0.1 mg/mL BSA). The mixture was incubated for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Discovery of JAK2/3 Inhibitors from Quinoxalinone-Containing Compounds

et al. 2022

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Janus kinases (JAKs) are involved in a wide variety of cell signaling associated with T-cell and B-cell mediated diseases. The pathogenesis of common lymphoid-derived diseases and leukemia cancer has been implicated in JAK2 and JAK3. Therefore, to decrease the risk of these diseases, targeting this pathway using JAK2/3 inhibitors could serve as a valuable research tool. Herein, we used a combination of the computational and biological approaches to identify the quinoxalinone-based dual inhibitors of JAK2/3. First, an in-house library of 49 quinoxalinones was screened by molecular docking. Then, the inhibitory activities of 17 screened compounds against both JAKs as well as against two human erythroleukemia cell lines, TF1 and HEL were examined. The obtained results revealed that several quinoxalinones could potentially inhibit JAK2/3, and among them, ST4j showed strong inhibition against JAKs with the IC 50 values of 13.00 ± 1.31 nM for JAK2 and 14.86 ± 1.29 nM for JAK3, which are better than ruxolitinib and tofacitinib. In addition, ST4j potentially inhibited TF1 cells (IC 50 of 15.53 ± 0.82 μM) and HEL cells (IC 50 of 17.90 ± 1.36 μM), similar to both tofacitinib ruxolitinib. Mechanistically, ST4j inhibited JAK2 autophosphorylation and induced cell apoptosis in dose- and time-dependent manners. From molecular dynamics simulations, ST4j was mainly stabilized by van der Waals interactions, and its hydroxyl group could form hydrogen bonds in the hinge region at residues S936 and R938 of JAK2. This research highlights the potential of ST4j to be a novel therapeutic agent for the treatment of lymphoid-derived diseases and leukemia cancer.

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“…Molecular modeling in combination to molecular dynamics simulation has been widely used in computer-aided drug design [ 23 , 24 ]. QSAR is one of the effective methods for predicting the activity of compounds when data and appropriate experimental facilities are lacking [25] . Whereas molecular docking is a very fast and efficient tool for predicting how a small molecule will have a conformational geometry on the active site of the target protein [26] .…”

Section: Introductionmentioning

confidence: 99%

Computational strategies towards developing novel SARS-CoV-2 Mpro inhibitors against COVID-19

Luo

Tong

Zhang

et al. 2022

Journal of Molecular Structure

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The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains to be a serious threat due to the lack of a specific therapeutic agent. Computational methods are particularly suitable for rapidly fight against SARS-CoV-2. This present research aims to systematically explore the interaction mechanism of a series of novel bicycloproline-containing SARS-CoV-2 M pro inhibitors through integrated computational approaches. We designed six structurally modified novel SARS-CoV-2 M pro inhibitors based on the QSAR study. The four designed compounds with higher docking scores were further explored through molecular docking, molecular dynamics (MD) simulations, free energy calculations, and residual energy contributions estimated by the MM-PBSA approach, with comparison to compound 23(PDB entry 7D3I). This research not only provides robust QSAR models as valuable screening tools for the development of anti-COVID-19 drugs, but also proposes the newly designed SARS-CoV-2 M pro inhibitors with nanomolar activities that can be potentially used for further characterization to treat SARS-CoV-2 virus.

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Potential tripeptides against the tyrosine kinase domain of human epidermal growth factor receptor (HER) 2 through computational and kinase assay approaches

Cited by 4 publications

References 39 publications

Identification of tripeptides against tyrosine kinase domain of EGFR for lung cancer cell inhibition by in silico and in vitro studies

Identification of tripeptides against tyrosine kinase domain of EGFR for lung cancer cell inhibition by in silico and in vitro studies

Discovery of JAK2/3 Inhibitors from Quinoxalinone-Containing Compounds

Computational strategies towards developing novel SARS-CoV-2 Mpro inhibitors against COVID-19

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