Computer-aided molecular design of new potential inhibitors of protein kinases using of 4-methyl-benzoic acid as a linker

Faryna, Aliaksandr; Kalinichenko, Еlena N.

doi:10.25177/jccmm.3.2.ra.577

Cited by 3 publications

(4 citation statements)

References 14 publications

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“…In the second experiment, all original ligand structures were preliminarily minimized using a GAFF force field, which aims to simulate constructing them from scratch. For a number of receptors, docking scores for native ligands were taken from our previous works [ 25 , 26 ]. The correctness of the reproduction of the experimental docking poses for original ligands was assessed visually by the comparison with the ligands contained in the PDB complexes.…”

Section: Resultsmentioning

confidence: 99%

“…Long electrostatic coupling was treated according to PME method. G_mmpbsa tool was used for MM-PBSA binding energy calculations [ 26 ]. To perform energy calculations, every twentieth frame of the final molecular dynamics trajectory was extracted, skipping the first 100 frames.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous work, we suggested to use a flexible 4-methylbenzamide linker to obtain new chemical compounds capable of inhibiting protein kinases. A number of the obtained derivatives of 4-methylbenzamide showed high biological activity in vitro and in silico [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors

Kalinichenko¹,

Faryna²,

Bozhok³

et al. 2021

IJMS

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A novel class of potential protein kinase inhibitors 7–16 was synthesized in high yields using various substituted purines. The most promising compounds, 7 and 10, exhibited inhibitory activity against seven cancer cell lines. The IC50 values for compounds 7 and 10 were 2.27 and 2.53 μM for K562 cells, 1.42 and 1.52 μM for HL-60 cells, and 4.56 and 24.77 μM for OKP-GS cells, respectively. In addition, compounds 7 and 10 dose-dependently induced the apoptosis and cell cycle arrest at G2/M phase, preventing the cell division of OKP-GS cells. Compounds 7, 9, and 10 showed 36–45% inhibitory activity against PDGFRα and PDGFRβ at the concentration of 1 μM. Molecular modeling experiments showed that obtained compounds could bind to PDGFRα as either type 1 (compound 7, ATP-competitive) or type 2 (compound 10, allosteric) inhibitors, depending on the substituent in the amide part of the molecule.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors

Kalinichenko¹,

Faryna²,

Bozhok³

et al. 2021

IJMS

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“…This work continues our previous studies on pharmacophore modeling and synthesis and the biological activities of potential type-2 PKIs. In our previous studies, based on the results of docking and molecular dynamics, we used the 4-methylbenzamide structural fragment as a basis for designing new chemical compounds that had pharmacophore similarity to imatinib, sorafenib and other known inhibitors [ 30 ]. These 4-methylbenzamide derivatives were able to inhibit protein kinases and block the growth of tumor cells in vitro [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity

Kalinichenko

Faryna

Bozhok

et al. 2023

CIMB

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In this work, fragments of isophthalic and terephthalic acids are proposed as a structural scaffold to develop potential inhibitors of protein kinases. Novel isophthalic and terephthalic acid derivatives were designed as type-2 protein kinase inhibitors, synthesized and subjected to physicochemical characterization. The screening of their cytotoxic actions against a panel of cell lines derived from different types of tumors (liver, renal, breast and lung carcinomas, as well as chronic myelogenous and promyelocytic leukemia) and normal human B lymphocyte, for the sake of comparison, was performed. Compound 5 showed the highest inhibitory activity against four cancer cell lines, K562, HL-60, MCF-7 and HepG2 (IC50 = 3.42, 7.04, 4.91 and 8.84 µM, respectively). Isophthalic derivative 9 revealed a high potency against EGFR and HER2, at the levels of 90% and 64%, respectively, being comparable to lapatinib at 10 µM. In general, tumor cell cultures were more sensitive to isophthalic acid derivatives than to terephthalic acid ones. In cell cycle studies, isophthalic analogue 5 showed a pronounced dose-dependent effect, and with the increase in its concentration up to 10.0 µM, the number of living cells decreased to 38.66%, while necrosis reached 16.38%. The considered isophthalic compounds had a similar docking performance to that of sorafenib against the VEGFR-2 (PDB id: 4asd, 3wze). The correct binding of compounds 11 and 14 with VEGFR-2 was validated using MD simulations and MM-GPSA calculations.

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Molecular modeling piloted analysis for semicarbazone derivative of curcumin as a potent Abl-kinase inhibitor targeting colon cancer

et al. 2021

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The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC50 value of 5.85 µM, which was sevenfold lower as compared to Curcumin’s IC50 of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy.

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Computer-aided molecular design of new potential inhibitors of protein kinases using of 4-methyl-benzoic acid as a linker

Abstract: Computer-aided molecular design of new potential inhibitors of protein kinases using of 4-methyl-benzoic acid as a linker(2019)Journal of Computational Chemistry & Molecular Modeling 3(2)pp:285-293

Cited by 3 publications

References 14 publications

Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors

Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors

Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity

Molecular modeling piloted analysis for semicarbazone derivative of curcumin as a potent Abl-kinase inhibitor targeting colon cancer

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