Computational Designing and Prediction of ADMET Properties of Four Novel Imidazole‐based Drug Candidates Inhibiting Heme Oxygenase‐1 Causing Cancers

Rahman, Md. Mijanur; Talukder, Asma; Akter, Rekha

doi:10.1002/minf.202060033

Cited by 6 publications

(3 citation statements)

References 61 publications

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“…There were also no π-π stacking interactions formed in the docked complexes. Thus, the in silico molecular docking study predicts that test ligand stylopine may be a potential compound as compared to the standard axitinib against the human VEGFR2 tyrosine domain (Rahman et al, 2021;Chabukswar et al, 2022). Hence, stylopine was further investigated on MG-63 cells using in-vitro methods.…”

Section: Molecular Docking Of Stylopine With Human Vegfr2 Kinasementioning

confidence: 99%

Stylopine: A potential natural metabolite to block vascular endothelial growth factor receptor 2 (VEGFR2) in osteosarcoma therapy

et al. 2023

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Vascular endothelial growth factor (VEGF) signals cell survival, cell migration, osteogenesis, cell proliferation, angiogenesis, and vascular permeability by binding to VEGF receptor 2 (VEGFR-2). Osteosarcoma is the most common primary bone cancer, majorly affects young adults. Activation of VEGFR-2 signaling is a therapeutic target for osteosarcoma. The present study aimed to evaluate the potency of stylopine in regulation of the VEGFR-2 signaling pathway and its anti-tumour effect human MG-63 osteosarcoma cells. The in silico study on benzylisoquinoline alkaloids was carried out for analyzing and shortlisting of compounds using a virtual screening, Lipinski’s rule, bioavailability graphical RADAR plot, pharmacokinetics, toxicity, and molecular docking studies. Among the benzylisoquinoline alkaloids, stylopine was selected and subjected to in-vitro studies against human MG-63 osteosarcoma cells. Various experiments such as MTT assay, EtBr/AO staining, mitochondrial membrane potential assessment, transwell migration assay, gene expression analysis by a quantitative real time polymerase chain reaction (qRT-PCR) method, SDS-PAGE followed by immunoblotting were performed to evaluate its anti-tumour effect as compared to standard axitinib. The MTT assay indicates that stylopine inhibits cell proliferation in MG-63 cells. Similarly, as confirmed by the EtBr/Ao staining method, the MMP assay indicates that stylopine induces mitochondrial membrane damage and apoptosis as compared to axitinib. Moreover, stylopine inhibits the VEGF-165 induced MG-63 cell migration by a trans-well migration assay. The immunoblotting and qRT-PCR analysis showed that stylopine inhibits the VEGF-165 induced VEGFR2 expression in MG-63 cells. It is concluded that stylopine has potential to regulate VEGFR2 and can inhibit osteosarcoma cells to offer a new drug candidate for the treatment of bone cancer in future.

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Section: Molecular Docking Of Stylopine With Human Vegfr2 Kinasementioning

confidence: 99%

Stylopine: A potential natural metabolite to block vascular endothelial growth factor receptor 2 (VEGFR2) in osteosarcoma therapy

et al. 2023

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“…Pharmacokinetics examines the behavior of a medicinal chemical in the body, specifically about its absorption (A), distribution (D), metabolism (M), and excretion (E). In silico, GIT, blood barrier penetration (Tian et al 2022 ), skin permeability, aqueous solubility [logS] (Dulsat et al 2023 ), acute oral toxicity, and cytochrome P450 2D6 inhibition (Tahir et al 2019 ), were used to calculate the ADMET properties of the chosen compounds (Rahman et al 2021 ). Therefore, before the clinical stage, drug candidate profiling is a practical drug discovery technique.…”

Section: Discussionmentioning

confidence: 99%

Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis

Sakhawat,

Khan,

Rehman

et al. 2023

AMB Expr

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Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin gene family gene that encodes proteins vital for the growth, maintenance, and survival of neurons in the nervous system. The study aimed to screen natural compounds against BDNF variant (V66M), which affects memory, cognition, and mood regulation. BDNF variant (V66M) as a target structure was selected, and Vitamin D, Curcumin, Vitamin C, and Quercetin as ligands structures were taken from PubChem database. Multiple tools like AUTODOCK VINA, BIOVIA discovery studio, PyMOL, CB-dock, IMOD server, Swiss ADEMT, and Swiss predict ligands target were used to analyze binding energy, interaction, stability, toxicity, and visualize BDNF-ligand complexes. Compounds Vitamin D3, Curcumin, Vitamin C, and Quercetin with binding energies values of − 5.5, − 6.1, − 4.5, and − 6.7 kj/mol, respectively, were selected. The ligands bind to the active sites of the BDNF variant (V66M) via hydrophobic bonds, hydrogen bonds, and electrostatic interactions. Furthermore, ADMET analysis of the ligands revealed they exhibited sound pharmacokinetic and toxicity profiles. In addition, an MD simulation study showed that the most active ligand bound favorably and dynamically to the target protein, and protein–ligand complex stability was determined. The finding of this research could provide an excellent platform for discovering and rationalizing novel drugs against stress related to BDNF (V66M). Docking, preclinical drug testing and MD simulation results suggest Quercetin as a more potent BDNF variant (V66M) inhibitor and forming a more structurally stable complex.

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“…They can be used as potential drugs for treating cancers and other diseases. Due to the multitarget activities of these inhibitors, we hope that these studies will also provide a reference and possibility for the study and treatment of other diseases in the future ( Rahman et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Chemical Reactivity and Optical and Pharmacokinetics Studies of 14 Multikinase Inhibitors and Their Docking Interactions Toward ACK1 for Precision Oncology

Srivastava

2022

Front. Chem.

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Activated Cdc42-associated kinase 1 (ACK1/TNK2) has a significant role in cell endocytosis, survival, proliferation, and migration. Mutations in ACK1 are closely associated with the occurrence and development of cancers. In this work, a conceptual density functional theory (CDFT)-based computational peptidology (CDFT-CP) method is used to study the chemical reactivity of 14 multikinase inhibitors. Optical properties of these inhibitors are studied by time-dependent density functional theory (TDDFT). Various biological and pharmacokinetic parameters are studied by Osiris, Molinspiration, and BOILED-Egg in SwissADME software tools. Physicochemical and biopharmaceutical (PCB), Salmonella typhimurium reverse mutation assay (AMES) mutagenicity, toxicity, and risk prediction are estimated by Simulations plus ADMET Predictor 10.2 software. MD simulations for an active model of ACK1 is carried out by the CABS-flex 2.0 web server, and potential binding pockets for ACK1 are searched using the PrankWeb server. SwissTargetPrediction is used to predict the potential targets for the multikinase inhibitors. Docking studies are carried out for ACK1–multikinase inhibitors using Autodock 4.2 software. Noncovalent interactions for ACK1–multikinase inhibitor complexes are studied using the Protein–Ligand Interaction Profiler (PLIP) server. Results indicated higher binding affinities and strong noncovalent interactions in ACK1–multikinase inhibitor complexes.

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Computational Designing and Prediction of ADMET Properties of Four Novel Imidazole‐based Drug Candidates Inhibiting Heme Oxygenase‐1 Causing Cancers

Cited by 6 publications

References 61 publications

Stylopine: A potential natural metabolite to block vascular endothelial growth factor receptor 2 (VEGFR2) in osteosarcoma therapy

Stylopine: A potential natural metabolite to block vascular endothelial growth factor receptor 2 (VEGFR2) in osteosarcoma therapy

Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis

Chemical Reactivity and Optical and Pharmacokinetics Studies of 14 Multikinase Inhibitors and Their Docking Interactions Toward ACK1 for Precision Oncology

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