Molecular interaction study of novel indoline derivatives with EGFR-kinase domain using multiple computational analysis

Palanivel, Suresh; Yli‐Harja, Olli; Kandhavelu, Meenakshisundaram

doi:10.1080/07391102.2021.1900917

Cited by 6 publications

(3 citation statements)

References 25 publications

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“…EGFR is the key regulator of various cellular events in many cancers, including in CRC. Our previous study has reported on the therapeutic role of HNPMI targeting EGFR and thus inferred it as a potential anti‐cancer agent against breast cancer (Palanivel et al, 2021 ). In our present analysis, we docked the atomic crystal structure of EGFR (PDB ID: 1MOX) to our lead indoline derivative, HNPMI.…”

Section: Resultsmentioning

confidence: 99%

A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL‐2/BAX and p53 in colon cancer

Kandhavelu

Kumar

Naidoo

et al. 2023

British J Pharmacology

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Background and PurposeColorectal cancer (CRC) is the second most devastating disease leading to higher mortality due to its heterogeneity and chemo‐resistance. Epidermal growth factor receptor (EGFR) is an effective therapeutic target and the focus of this study. Polyphenols modulate several key signaling mechanisms including EGFR‐signaling associated with anti‐proliferative and anti‐metastatic properties.Experimental approachUsing ligand‐ and structure‐based cheminformatics we developed three potent, selective alkylaminophenols, THTMP, THMPP, and HNPMI. These alkylaminophenols, were assessed for EGFR interaction, EGFR‐pathway modulation, cytotoxic and apoptosis induction, caspase activation, transcriptional and translational regulation. Finally, lead compound was evaluated for efficacy in the xenograft mice model.Key ResultsWe identify that alkylaminophenols as an effective anti‐EGFR compound against different grades of CRC. HNPMI exhibited the least IC50 on CRC cells and potential cytotoxicity effect on other tumour cells too. Modulation of EGFR pathway downregulated the osteopontin, survinin and cathepsin S proteins, thus leading to apoptosis. Furthermore, cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered several apoptotic‐related proteins including Caspase 3, BCL‐2, and p53, which were also validated at the level of RNA and protein. HNPMI significantly downregulated the crucial proteins associated with oncogenesis in CRC cells. Further, pre‐clinical validation in xenograft mice confirmed the potential of HNPMI in reducing the relative tumor volume.Conclusion and implicationsHNPMI is the promising EGFR inhibitor for clinical translation. HNPMI regulates apoptosis and oncogenesis by modulating BCL‐2/BAX and p53 in CRC, thus suggesting it as a therapeutic drug target for treating CRC.

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Section: Resultsmentioning

confidence: 99%

A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL‐2/BAX and p53 in colon cancer

Kandhavelu

Kumar

Naidoo

et al. 2023

British J Pharmacology

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“…Three-dimensional molecular electrostatic potential (3D MESP) maps were also obtained from the optimized structures [ 44 , 45 ]. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies, which determine chemical reactivity [ 9 , 10 , 11 , 46 , 47 , 48 , 49 ], are presented in the Supplementary Data section . Discussions of the global reactivity descriptors, such as the ionization potential (I), electron affinity (A), chemical potential (μ), electronegativity (χ), global hardness (η), global softness (S), and global electrophilicity (ω) values [ 12 , 13 , 14 , 16 ], are also presented in the Supplementary Data section .…”

Section: Methodsmentioning

confidence: 99%

“…To determine the free energy of binding for compounds 1 – 8 and standard drugs in the respective complexes, post-docking energy minimization studies were performed using Prime molecular mechanics-generalized Born surface area (MM-GB/SA) in Schrödinger 2022-1. The energy for the minimized XP docked pose of ligand–receptor complexes was calculated using the OPLS4 force field and generalized Born/surface area (GB/SA) continuum VSGB 2.0 solvent model [ 48 ].…”

Section: Methodsmentioning

confidence: 99%

Cu(II)-Catalysed Hydrocarboxylation of Imines Utilizing CO2 to Synthesize α-Unsaturated Aminocarboxylic Acids

Gordon

Hosten²,

Ogunlaja³

2022

Pharmaceuticals

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Here, we report the Cu(II)-photocatalysed hydrocarboxylation of imines (C=N) from a series of synthesized Schiff Base derivatives, namely (E)-1-(4-((4-methylbenzylidene)amino)phenyl)ethanone, (E)-1-(3-((5-bromo-2-hydroxybenzylidene)amino)phenyl)ethanone, (E)-4-((5-bromo-2-hydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, and (E)-1,5-dimethyl-4-((4-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-one, with carbon dioxide (CO2) to generate disubstituted amino acids. Under mild conditions (atmospheric pressure of CO2, room temperature, and 30 W Blue LED light), good to excellent yields confirming the formation of substituted amino acid unsaturated acid derivatives were obtained. Single crystal X-ray diffraction (SC-XRD) and UV-Vis diffuse reflectance spectroscopy (UV-Vis-DRS) confirmed the square pyramidal geometry of the Cu(II) photocatalyst. Docking and DFT calculations of the substituted amino acid unsaturated acid derivatives showed their potential as antimicrobial molecules.

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Design and Self Assembly of Tri-Terpene Peptide Conjugates and Their Interactions with EGFR and EGFR Mutant Receptors: An In Silico and In Vitro Study

Rico,

Goncalves,

Hunt

et al. 2023

Int J Pept Res Ther

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Molecular interaction study of novel indoline derivatives with EGFR-kinase domain using multiple computational analysis

Cited by 6 publications

References 25 publications

A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL‐2/BAX and p53 in colon cancer

A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL‐2/BAX and p53 in colon cancer

Cu(II)-Catalysed Hydrocarboxylation of Imines Utilizing CO2 to Synthesize α-Unsaturated Aminocarboxylic Acids

Design and Self Assembly of Tri-Terpene Peptide Conjugates and Their Interactions with EGFR and EGFR Mutant Receptors: An In Silico and In Vitro Study

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