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

Rodrigues, Fiona Concy; Hari, Gangadhar; Pai, K. S. R.; Suresh, Akhil; Nayak, Usha Yogendra; Anilkumar, N.; Thakur, Goutam

doi:10.1007/s13205-021-03051-9

Cited by 7 publications

(5 citation statements)

References 64 publications

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“…The compounds 3,5-Bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(substituted phenoxy)ethanones ( 3b,c ) were reported for the first time in the current investigation and they demonstrated promising antiproliferative activity against 5 dozen cancer cell lines derived from nine diverse panels. Some of the curcumin analogues reported earlier showed IC50 values of 16.71 (curcumin pyrazole) and 5.85 µM (curcumin semicarbazide) in an SRB assay against the HCT 116 cell line, while our compounds 3b and 3c displayed superior anticancer activity with GI 50 values of 0.386 and 0.416 µM, respectively [ 62 ]. The curcumin analogue 3b was found to be moderately selective against the leukemia panel with an SR of 4.59.…”

Section: Discussionmentioning

confidence: 95%

Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues

Ahsan¹,

Choudhary²,

Ali

et al. 2022

Plants

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With 19.3 million new cases and almost 10 million deaths in 2020, cancer has become a leading cause of death today. Curcumin and its analogues were found to have promising anticancer activity. Inspired by curcumin’s promising anticancer activity, we prepared three semi-synthetic analogues by chemically modifying the diketone function of curcumin to its pyrazole counterpart. The curcumin analogues (3a–c) were synthesized by two different methods, followed by their DFT analyses to study the HOMO/LUMO configuration to access the stability of compounds (∆E = 3.55 to 3.35 eV). The curcumin analogues (3a–c) were tested for antiproliferative activity against a total of five dozen cancer cell lines in a single (10 µM) and five dose (0.001 to 100 µM) assays. 3,5-Bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(phenoxy)ethanone (3b) and 3,5-bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(2,4-dichlorophenoxy)ethanone (3c) demonstrated the most promising antiproliferative activity against the cancer cell lines with growth inhibitions of 92.41% and 87.28%, respectively, in a high single dose of 10 µM and exhibited good antiproliferative activity (%GIs > 68%) against 54 out of 56 cancer cell lines and 54 out of 60 cell lines, respectively. The compound 3b and 3c demonstrated the most potent antiproliferative activity in a 5-dose assay with GI50 values ranging between 0.281 and 5.59 µM and 0.39 and 0.196 and 3.07 µM, respectively. The compound 3b demonstrated moderate selectivity against a leukemia panel with a selectivity ratio of 4.59. The HOMO-LUMO energy-gap (∆E) of the compounds in the order of 3a > 3b > 3c, was found to be in harmony with the anticancer activity in the order of 3c ≥ 3b > 3a. Following that, all of the curcumin analogues were molecular docked against EGFR, one of the most appealing targets for antiproliferative activity. In a molecular docking simulation, the ligand 3b exhibited three different types of interactions: H-bond, π-π-stacking and π-cationic. The ligand 3b displayed three H-bonds with the residues Met793 (with methoxy group), Lys875 (with phenolic group) and Asp855 (with methoxy group). The π-π-stacking interaction was observed between the phenyl (of phenoxy) and the residue Phe997, while π-cationic interaction was displayed between the phenyl (of curcumin) and the residue Arg841. Similarly, the ligand 3c displayed five H-bonds with the residue Met793 (with methoxy and phenolic groups), Lys845 (methoxy group), Cys797 (phenoxy oxygen), and Asp855 (phenolic group), as well as a halogen bond with residue Cys797 (chloro group). Furthermore, all the compound 3a–c demonstrated significant binding affinity (−6.003 to −7.957 kcal/mol) against the active site of EGFR. The curcumin analogues described in the current work might offer beneficial therapeutic intervention for the treatment and prevention of cancer. Future anticancer drug discovery programs can be expedited by further modifying these analogues to create new compounds with powerful anticancer potentials.

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Section: Discussionmentioning

confidence: 95%

Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues

Ahsan¹,

Choudhary²,

Ali

et al. 2022

Plants

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“…To assess the pharmacological potential of the investigated compounds, an ADME/T study was carried out. The Schrödinger software's Qik‐prop module [ 48 ] was used to forecast the outcomes and interactions of the synthesized compounds in human metabolism.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, biological activities, and molecular docking studies of triazolo[4,3‐b]triazine derivatives as a novel class of α‐glucosidase and α‐amylase inhibitors

Seyfi,

Salarinejad,

Moghimi

et al. 2024

Archiv der Pharmazie

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In diabetes mellitus, amylase and glucosidase enzymes are the primary triggers. The main function of these enzymes is to break macromolecules into simple sugar units, which directly affect blood sugar levels by increasing blood permeability. To overcome this metabolic effect, there is a need for a potent and effective inhibitor capable of suppressing the enzymatic conversion of sugar macromolecules into their smaller units. Herein, we reported the discovery of a series of substituted triazolo[4,3‐b][1,2,4]triazine derivatives as α‐glucosidase and α‐amylase inhibitors. All target compounds demonstrated significant inhibitory activities against α‐glucosidase and α‐amylase enzymes compared with acarbose as the positive control. The most potent compound 10k, 2‐[(6‐phenyl‐[1,2,4]triazolo[4,3‐b][1,2,4]triazin‐3‐yl)thio]‐N‐[4‐(trifluoromethyl)phenyl]acetamide, demonstrated IC50 values of 31.87 and 24.64 nM against α‐glucosidase and α‐amylase enzymes, respectively. To study their mechanism of action, kinetic studies were also done, which determined the mode of inhibition of both enzymes. Molecular docking was used to confirm the binding interactions of the most active compounds.

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“…Molecular electrostatic potential depicts the electron density distribution and chemical reactivity around the analyzed phytochemical. The mathematical formulations that define these descriptors can be described as follows [38][39][40] Molecular mechanics-generalized Born surface area (MM-GBSA) is a significant approach to estimating the binding free energy of the protein-ligand complex [41,42]. In addition, this approach is useful in the validation of docking results to remove significant false positives in the protein-ligand interaction.…”

Section: Density Functional Theorymentioning

confidence: 99%

Network-Derived Radioresistant Breast Cancer Target with Candidate Inhibitors from Brown Algae: A Sequential Assessment from Target Selection to Quantum Chemical Calculation

Sivakumar,

Ahmad,

Emran

et al. 2023

Marine Drugs

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Despite significant progress in early detection and treatment, a few aggressive breast cancers still exhibit resistance to therapy. This study aimed to identify a therapeutic target for radioresistant breast cancer (RRbc) through a protein network from breast cancer genes and to evaluate potent phytochemicals against the identified target. Our approach includes the integration of differential expression genes from expression datasets to create a protein network and to use survival analysis to identify the crucial RRbc protein in order to discover a therapeutic target. Next, the phytochemicals sourced from brown algae were screened through molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation, MM-GBSA, and quantum mechanics against the identified target. As a result of our protein network investigation, the proto-oncogene c-KIT (KIT) protein was identified as a potent radioresistant breast cancer target. Further, phytochemical screening establishes that nahocol-A1 from brown algae has high binding characteristics (−8.56 kcal/mol) against the KIT protein. Then, quantum chemical analysis of nahocol-A1 provided insights into its electronic properties favorable for protein binding. Also, MD simulation comprehends the conformational stability of the KIT–nahocol-A1 complex. Overall, our findings suggest nahocol-A1 could serve as a promising therapeutic candidate for radioresistant breast cancer.

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

Cited by 7 publications

References 64 publications

Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues

Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues

Synthesis, biological activities, and molecular docking studies of triazolo[4,3‐b]triazine derivatives as a novel class of α‐glucosidase and α‐amylase inhibitors

Network-Derived Radioresistant Breast Cancer Target with Candidate Inhibitors from Brown Algae: A Sequential Assessment from Target Selection to Quantum Chemical Calculation

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