Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

Molecules, Год журнала: 2022, Номер 27(14), С. 4606 - 4606

Опубликована: Июль 19, 2022

A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact catalytic pocket. The ability of congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, bind enzyme demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established excellent binding 10 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed proper a total exact energy -38.36 Kcal/Mol. also revealed crucial amino acids in through free decomposition and declared interactions variation inside via Protein-Ligand Interaction Profiler (PLIP). Being new, its structure optimized DFT. DFT mode VEGFR-2. ADMET (in silico) profiling indicated examined compound's acceptable range drug-likeness. synthesized condensation N-(4-(hydrazinecarbonyl)phenyl)benzamide N-(4-acetylphenyl)nicotinamide, where carbonyl group has been replaced imine group. in-vitro were consonant obtained silico results prohibited IC50 value 51 nM. Compound showed effects against MCF-7 HCT 116 cancer cell lines values 8.25 6.48 μM, revealing magnificent selectivity indexes 12.89 16.41, respectively.

Язык: Английский

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Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(13), С. 6912 - 6912

Опубликована: Июнь 21, 2022

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising SARS-CoV-2 main protease (Mpro) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, molecular structure similarity study done with PRD_002214, co-crystallized ligand Mpro (PDB ID: 6LU7), favored thirty Subsequently, fingerprint respect to PRD_002214 resulted election sixteen compounds (7, 128, 130, 156, 157, 158, 180, 184, 203, 204, 210, 237, 264, 276, 277, 278). Then, results docking versus PDB 6LU7 eight (128, 278) based on their binding affinities. toxicity studies for revealed that all them have good profiles. Finally, dynamic (MD) simulation experiments carried out 278, which exhibited best modes Mpro. MD tests luteoside (130) has greatest potential inhibit protease.

Язык: Английский

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The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

Processes, Год журнала: 2022, Номер 10(7), С. 1391 - 1391

Опубликована: Июль 17, 2022

Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1H-indole derivative (compound 7) was designed. The inhibitory potential designed compound revealed via molecular docking study that showed appropriate binding. Then, MD simulation (six studies) over period 100 ns performed confirm precise binding and optimum energy. Additionally, MM-GBSA reaffirmed perfect binding, exhibiting total energy −40.38 Kcal/Mol. experiments named essential amino acids in protein–ligand interaction, employing decomposition revealing diversity interactions 7 inside VEGFR-2 enzyme. As is new, DFT were utilized for structure optimization. results validated coherent interaction with A good value drug-likeness acknowledged silico ADMET studies. Interestingly, experimental vitro prohibitory better than sorafenib, demonstrating an IC50 25 nM. Notably, strong effects 10 against two cancer cell lines (MCF-7 HCT 116) established values 12.93 11.52 μM, disclosing high selectivity indexes 6.7 7.5, respectively.

Язык: Английский

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Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

Molecules, Год журнала: 2022, Номер 27(15), С. 5047 - 5047

Опубликована: Авг. 8, 2022

This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative previous concerned with development VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast (MCF-7), colorectal carcinoma (HCT116), hepatocellular (HepG2). The also kinase activity. biological testing fallouts showed that compound

Язык: Английский

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A Multistage In Silico Study of Natural Potential Inhibitors Targeting SARS-CoV-2 Main Protease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(15), С. 8407 - 8407

Опубликована: Июль 29, 2022

Among a group of 310 natural antiviral metabolites, our team identified three compounds as the most potent inhibitors against SARS-CoV-2 main protease (PDB ID: 5R84), Mpro. The are sattazolin and caprolactin A B. validated multistage in silico study was conducted using several techniques. First, molecular structures selected metabolites were compared with that GWS, co-crystallized ligand Mpro, structural similarity study. aim this to determine thirty similar (10%) may bind Mpro GWS. Then, docking pharmacophore studies led choice five exhibited good binding modes fit values generated model. them, chosen according ADMET studies. promising inhibitor determined by toxicity DFT be (292). Finally, dynamics (MD) simulation performed for confirm obtained results understand thermodynamic characteristics binding. It is hoped accomplished could represent positive step battle COVID-19 through further vitro vivo on compounds.

Язык: Английский

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Ligand and Structure-Based In Silico Determination of the Most Promising SARS-CoV-2 nsp16-nsp10 2′-o-Methyltransferase Complex Inhibitors among 3009 FDA Approved Drugs

Molecules, Год журнала: 2022, Номер 27(7), С. 2287 - 2287

Опубликована: Март 31, 2022

As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2'-o-methyltransferase (2'OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential examined compounds (PDB ID: (6W4H) was conducted multi-step screening approach. At beginning, molecular fingerprints experiment with SAM (S-Adenosylmethionine), co-crystallized ligand targeted enzyme, unveiled resemblance 147 drugs. Then, structural similarity recommended 26 Therefore, docked 2'OMTase to reveal effect promising (Protirelin, (1187), Calcium folinate (1913), Raltegravir (1995), Regadenoson (2176), Ertapenem (2396), Methylergometrine (2532), and Thiamine pyrophosphate hydrochloride (2612)). Out ligands, (2396) showed an ideal binding mode like that (SAM). It occupied all sub-pockets active site bound crucial amino acids. Accordingly, some MD simulation experiments (RMSD, RMSF, Rg, SASA, H-bonding) have been for 2'OMTase-Ertapenem complex over 100 ns. performed verified correct exhibiting low energy optimal dynamics. Finally, MM-PBSA studies indicated bonded advantageously protein free value -43 KJ/mol. Furthermore, analysis revealed essential acids served positively binding. achieved results bring hope find treatment COVID-19 via vitro vivo pointed

Язык: Английский

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Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 1389 - 1403

Опубликована: Май 16, 2022

A library of modified VEGFR-2 inhibitors was designed as inhibitors. Virtual screening conducted for the hypothetical using in silico docking, ADMET, and toxicity studies. Four compounds exhibited high affinity against an acceptable range drug-likeness. These were synthesised subjected to vitro cytotoxicity assay two cancer cell lines besides inhibitory determination. Compound D-1 showed cytotoxic activity HCT-116 cells almost double that sorafenib. Compounds A-1, C-6, good IC50 values VEGFR-2. markedly increased levels caspase-8 BAX expression decreased anti-apoptotic Bcl-2 level. Additionally, compound caused cycle arrest at pre-G1 G2-M phases induced apoptosis both early late apoptotic stages. level TNF-α IL6 inhibited IL6. MD simulations studies performed over 100 ns.

Язык: Английский

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In vitroand computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-M^Proinhibitors

RSC Advances, Год журнала: 2022, Номер 12(41), С. 26895 - 26907

Опубликована: Янв. 1, 2022

An essential target for COVID-19 is the main protease of SARS-CoV-2 (Mpro). With objective targeting this receptor, a novel set pyrido[1,2-a]pyrrolo[2,3-d]pyrimidines with terminal carboxamide fragments was designed, synthesized, and considered as an initial motif creation effective pan-coronavirus inhibitors. Accordingly, nine derivatives (21-29) have been introduced in vitro assay to evaluate their antiviral activity cytotoxicity effect against virus using Vero cells. The obtained data revealed that majority these showed potent cellular anti-COVID-19 prevent viral growth by more than 90% at two different concentrations weak or even no detectable cytotoxic on Extensive molecular docking simulations highlighted proper non-covalent interaction new compounds within binding pocket Mpro potential activity. In all synthesized indicated 25 29 promising inhibitory IC50 values low micromolar concentrations. dynamic simulation results predicted stability compound cavity hence supported high shown assay. These suggested merit further investigations drug candidates management SARS-CoV-2.

Язык: Английский

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Discovery of new quinoline and isatine derivatives as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative, docking and MD simulation studies

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер 41(21), С. 11535 - 11550

Опубликована: Янв. 8, 2023

A new set of quinoline and isatine derivatives were synthesized as antiangiogenic VEGFR-2 inhibitors. On a biological level, the in vitro ability obtained candidates to inhibit was found be strong with IC50 values range 76.64-175.50 nM. To investigate cytotoxicity safety, all compounds tested against panel four cancer cell lines (A549, Caco2, HepG2 MDA) well two normal (Vero WI-38). Interestingly, compound 12 exhibited noticeable A549, Caco2 MDA 5.40, 0.58 0.94 µM, respectively. These results better comparable that doxorubicin (0.70, 0.82 0.90 respectively) more than three folds higher selectivity index lines. Compound 9 prevented healing cells at low concentration. Also, compound's potential induce programmed death Caco-2 proved through significant down regulating expression Bcl2, Bcl-xl Survivin addition slight upregulation TGF-β gene. The cycle analysis indicated arrested G2/M phase. molecular docking studies revealed correct binding targeted similar sorafenib. Furthermore, MD experiments validated over 100 ns, MM-PBSA confirmed precise optimum energy. Finally, ADMET showed general drug-likeness safety compounds.Communicated by Ramaswamy H. Sarma.

Язык: Английский

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Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers

Computational Biology and Chemistry, Год журнала: 2023, Номер 107, С. 107953 - 107953

Опубликована: Авг. 30, 2023

Язык: Английский

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