(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide: A Novel Pyridine Derivative for Inhibiting Vascular Endothelial Growth Factor Receptor-2: Synthesis, Computational, and Anticancer Studies

Molecules, Journal Year: 2022, Volume and Issue: 27(22), P. 7719 - 7719

Published: Nov. 9, 2022

(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide (compound 10) was designed as an antiangiogenic VEGFR-2 inhibitor with the essential pharmacophoric structural properties to interact catalytic pocket of VEGFR-2. The derivative synthesized, and its structure confirmed through Ms, elemental, 1H, 13C spectral data. potentiality pyridine bind inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme indicated by molecular docking assessments. In addition, six dynamic (MD) experiments proved correct binding over 100 ns. Additionally, mechanics energies, combined generalized born surface area (MM-GBSA) analysis, identified precise optimum energy. To explore stability reactivity derivative, density functional theory (DFT) calculations, including electrostatic potential maps total electron density, were carried out. absorption, distribution, metabolism, excretion, toxicity (ADMET) analysis demonstrated general likeness safety. compound synthesized evaluate effects against protein, cancer, normal cells. in vitro results concordant silico results, because new displayed inhibition IC50 value 65 nM potent cytotoxic hepatic (HepG2) breast (MCF-7) cancer cell lines values 21.00 26.10 μM, respectively; additionally, it exhibited high selectivity indices (W-38) 1.55 1.25, respectively. obtained present 10 a lead for further biological investigation chemical modifications.

Language: Английский

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Exploring binding potential of two new indole alkaloids from Nauclea officinalis against third and fourth generation EGFR: druglikeness, in silico ADMET, docking, DFT, molecular dynamics simulation, and MMGBSA study

Natural Product Research, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 8

Published: Jan. 11, 2024

This study investigates the anti-cancer potential of recently discovered indole alkaloids from Nauclea Officinalis against third and fourth-generation EGFR mutations using computational tools. Through ADMET profiling, druglikeness prediction, docking, simulations, we assessed their pharmacokinetics, binding interactions, stability. Promising affinity were observed, particularly for (±)-19-O-butylangustoline, which demonstrated stronger both mutants. MD simulations confirmed stable with (±)-19-O-butylangustoline exhibiting highest These findings highlight these as agents, warranting further optimisation therapeutic development. informs through insights into molecular properties energetics.

Language: Английский

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An outlook of docking analysis and structure-activity relationship of pyrimidine-based analogues as EGFR inhibitors against non-small cell lung cancer (NSCLC)

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(18), P. 9795 - 9811

Published: Aug. 29, 2023

AbstractAlmost 80% of lung cancer diagnoses each year correspond to non-small cell (NSCLC). The percentage NSCLC with EGFR overexpression ranges from 40% 89%, squamous tumors showing the greatest rates (89%) and adenocarcinomas lowest (41%). Therefore, in therapy, blocking EGFR-driven pathway by inhibiting intracellular tyrosine kinase domain has exhibited significant improvement. In this view, several small molecules particularly pyrimidine/fused pyrimidine scaffolds were intended for molecular hybridization develop EGFR-TK inhibitors. However, associated limitation such as resistance genetic mutation along adverse effects, constrained long-term treatment effectiveness medication. recent years, derivatives uncovered potential TKIs. present review summarised research progress TKIs dazed structure-activity relationship, biological evaluation, comparative docking studies compounds. We have added analysis followed simulation study against four different PDBs strengthen already existing research. Docking unfolded that compound 14 resulted noticeable all PDB managed interact some crucial amino acid residues. From a future perspective, researchers must more selective inhibitor, can selectively target mutation. Our will support medicinal chemists direction development novel pyrimidine-based TKIs.Communicated Ramaswamy H. SarmaKeywords: TKIsdockingmutationstructural-activity relationshipcancerpyrimidine Disclosure statementThe authors co-authors confirmed they do not any personal relationships or financial competition could seemed affect current reported work.Additional informationFundingCurrent work was sponsored ICMR (No. 5/13/12/2020/NCD-III No. 5/13/79/2020/NCD-III) projects Acharya & B M Reddy college Pharmacy, Bengaluru.

Language: Английский

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New Theobromine Derivatives Inhibiting VEGFR-2: Design, Synthesis, Antiproliferative, Docking and Molecular Dynamics Simulations

Future Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(14), P. 1233 - 1250

Published: July 1, 2023

Background: VEGFR-2 is one of the most effective targets in cancer treatment. Aim: The design and semi-synthesis new theobromine derivatives as potential inhibitors. Methods: In vitro silico evaluation synthesized compounds. Results: Compound 5b demonstrated excellent antiproliferative inhibitory effects with significant apoptotic activity. It modulated immune response by increasing IL-2 reducing TNF-α levels. Docking molecular dynamics simulations revealed compound’s binding affinity VEGFR-2. Lastly, computational absorption, distribution, metabolism, excretion toxicity studies indicated high compound for drug development. Conclusion: could be a promising anticancer agent targeting

Language: Английский

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A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

Life, Journal Year: 2023, Volume and Issue: 13(1), P. 191 - 191

Published: Jan. 9, 2023

A new lead compound has been designed as an antiangiogenic EGFR inhibitor that the pharmacophoric characteristics to bind with catalytic pocket of protein. The is a (para-chloro)acetamide derivative alkaloid, theobromine, (T-1-PCPA). At first, we started deep density functional theory (DFT) calculations for T-1-PCPA confirm and optimize its 3D structure. Additionally, DFT studies identified electrostatic potential, global reactive indices total states expecting high level reactivity T-1-PCPA. Secondly, affinity inhibit protein was studied confirmed through detailed structure-based computational including molecular docking against EGFRWT EGFRT790M, Molecular dynamics (MD) over 100 ns, MM-GPSA PLIP experiments. Before preparation, ADME toxicity profiles have investigated safety general drug-likeness predicted. Accordingly, semi-synthesized scrutinize proposed design obtained in silico results. Interestingly, inhibited vitro IC50 value 25.35 nM, comparing erlotinib (5.90 nM). growth A549 HCT-116 malignant cell lines values 31.74 20.40 µM, respectively, expressed 6.73 16.35 respectively.

Language: Английский

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Design, in silico studies and biological evaluation of novel chalcones tethered triazolo[3,4-a]isoquinoline as EGFR inhibitors targeting resistance in non-small cell lung cancer

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 4, 2024

Language: Английский

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Phenolic compounds of Theobroma cacao L. show potential against dengue RdRp protease enzyme inhibition by In-silico docking, DFT study, MD simulation and MMGBSA calculation

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(3), P. e0299238 - e0299238

Published: March 14, 2024

Background Currently, there is no antiviral medication for dengue, a potentially fatal tropical infectious illness spread by two mosquito species, Aedes aegypti and albopictus . The RdRp protease of dengue virus potential therapeutic target. This study focused on the in silico drug discovery inhibitors. Methods To assess inhibitory activity 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, range computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, molecular dynamics (MD) simulations. aim these studies was to confirm stability ligand-protein complex binding pose identified during docking experiment. Results Twenty-one compounds found have possible activities DENV according data, they had affinity ≥-37.417 kcal/mol DENV3- enzyme as compared reference compound panduratin A. Additionally, investigation produced four hit that subjected screening obtain lead compound, catechin. Based ELUMO, EHOMO, band energy gap, DFT calculations showed strong electronegetivity, favouravle global softness chemical reactivity with considerable intra-molecular charge transfer between electron-donor electron-acceptor groups MD simulation result also demonstrated favourable RMSD, RMSF, SASA H-bonds at pocket catechin Conclusion According present findings, high sufficient drug-like properties appropriate profiles. Moreover, further supported action candidate. Therefore, vitro vivo research cocoa its phytochemical should be taken into consideration develop inhibitor.

Language: Английский

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Discovery of New VEGFR-2 Inhibitors: Design, Synthesis, Anti-Proliferative Evaluation, Docking, and MD Simulation Studies

Molecules, Journal Year: 2022, Volume and Issue: 27(19), P. 6203 - 6203

Published: Sept. 21, 2022

Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners synthesized possessing the pharmacophoric essential features to bind correctly with active pocket. All members evaluated for their cytotoxic and inhibitory potentialities. Compound 6 was most potent showingIC50 values of 9.3 ± 0.02 7.8 0.025 µM against HCT-116 HepG-2 cells, respectively, IC50 60.83 nM regarding enzyme inhibition. arrested growth cells at pre-G1 G2-M phases. Further, it induced both early late apoptosis. Additionally, compound caused a significant decrease in TNF-α IL6 by 66.42% 57.34%, respectively. considered compounds had similar docking performances that sorafenib (PDB ID: 2OH4). correct binding validated using MD simulations, MM-GPSA calculations.

Language: Английский

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Design, synthesis, anticancer evaluation, in silico docking and ADMET analysis of novel indole-based thalidomide analogs as promising immunomodulatory agents

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 41(24), P. 15106 - 15123

Published: March 8, 2023

In the present work, novel 16 indole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The compounds evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3 MCF-7 cell lines. Generally, opened of glutarimide ring exhibited higher than closed ones. Compounds 21a-b 11d,g showed strong potencies all tested lines with IC50 values ranging from 8.27 25.20 µM comparable that (IC50 32.12 76.91 µM). most active further in vitro via estimation human tumor necrosis factor alpha (TNF-α), caspase-8 (CASP8), vascular endothelial growth (VEGF), nuclear kappa-B P65 (NF-κB P65) HCT-116 cells. Thalidomide was used as a positive control. 11g, 21a 21b remarkable significant reduction TNF-α. Furthermore, elevation CASP8 levels. 11g significantly inhibited VEGF. addition, derivatives 11d, decrease level NF-κB p65. Moreover, our good silico docking ADMET profile.Communicated by Ramaswamy H. Sarma.

Language: Английский

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Anticancer derivative of the natural alkaloid, theobromine, inhibiting EGFR protein: Computer-aided drug discovery approach

PLoS ONE, Journal Year: 2023, Volume and Issue: 18(3), P. e0282586 - e0282586

Published: March 9, 2023

A new semisynthetic derivative of the natural alkaloid, theobromine, has been designed as a lead antiangiogenic compound targeting EGFR protein. The is an ( m -tolyl)acetamide theobromine derivative, T-1-MTA ). Molecular Docking studies have shown great potential for to bind EGFR. MD (100 ns) verified proposed binding. By MM-GBSA analysis, exact binding with optimal energy was also identified. Then, DFT calculations were performed identify stability, reactivity, electrostatic potential, and total electron density . Furthermore, ADMET analysis indicated ’s general likeness safety. Accordingly, synthesized be examined in vitro Intriguingly, inhibited protein IC 50 value 22.89 nM demonstrated cytotoxic activities against two cancer cell lines, A549, HCT-116, values 22.49, 24.97 μM, respectively. Interestingly, normal WI-38, very high (55.14 μM) indicating selectivity degrees 2.4 2.2, flow cytometry A549 treated showed significantly increased ratios early apoptosis (from 0.07% 21.24%) well late 0.73% 37.97%).

Language: Английский

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