Pharmacophore and Docking Guided Virtual Screening Study for Discovery of Type I Inhibitors of VEGFR-2 Kinase

Bhojwani, Heena R.; Joshi, Urmila J.

doi:10.2174/1386207319666161214112536

Cited by 12 publications

(4 citation statements)

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“…The default setting of 10 Å on each side was used for the bounding box. According to these specifications for the center and size the final enclosing box was generated (20,21). No constraints were used.…”

Section: Introductionmentioning

confidence: 99%

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Studies in molecular modeling, in-vitro CDK2 inhibition and antimetastatic activity of some synthetic flavones

Wagal

Joshi

Joshi³

et al. 2021

Front Biosci

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Introduction 3. Materials and methods 3.1. In silico studies on CDK2 3.1.1. Molecular docking 3.1.2. Molecular dynamics simulation 3.2. In vitro CDK2 inhibition assay 3.3. In vitro evaluation of antimetastatic potential on B16F10 cell line 3.3.1. Determination of cell viability by MTT assay 3.3.1.1. Preparation of solutions for compounds for MTT assay 3.3.1.2. MTT assay 3.3.2. Preparation of dilutions for colony formation assay, wound scratch assay, and Leighton tube studies 3.3.3. Colony formation assay 3.3.4. Wound healing assay 3.3.5. Determination of cellular morphology by Leighton tube assay 4. Results and Discussion 4.1 In silico studies on CDK2 4.1.1. Molecular docking 4.1.1.1. Validation of docking protocol 4.1.1.2. Docking studies of synthetic flavones 4.1.2. Molecular dynamics simulation 4.2. In vitro CDK2 inhibition assay 4.3. In vitro studies on B16F10 cell line 4.3.1. Synthesized flavones exert cytotoxicity & inhibit the proliferation of B16F10 cells 4.3.2. Synthesized flavones hamper the formation of colonies in B16F10 melanoma 4.3.3. Synthesized flavones inhibit cellular migration in wound scratch assay 4.3.4. Synthesized flavones initiate changes in the morphology of B16F10 cells 5. Conclusion CDK2 Inhibition and antimetastatic effect of flavones 665

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Section: Introductionmentioning

confidence: 99%

“…No constraints were used. The docking protocol was validated for CDK2 by removing the inhibitor from their complexes, re-docking and calculating root mean square deviation (RMSD) (20)(21)(22)(23)(24). The prepared ligands viz.…”

Section: Introductionmentioning

confidence: 99%

Studies in molecular modeling, in-vitro CDK2 inhibition and antimetastatic activity of some synthetic flavones

Wagal

Joshi

Joshi³

et al. 2021

Front Biosci

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“…The docking method was validated by extracting and accurately re-docking the co-crystallized ligand into the active site, using unchanged grid parameters and protocols. The precision of the docking was quantified by calculating the root mean square deviation (RMSD) between the original co-crystallized ligand and the re-docked ligand [24].…”

Section: Molecular Docking and Molecular Interaction Visualizationmentioning

confidence: 99%

Molecular Dynamics and Binding Energetics of Fluspirilene With BACE1: Implications for Alzheimer's Disease Intervention

Bhattacharya,

Bhattacharjee,

Chakraborty

et al. 2024

Peptide Science

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Alzheimer's disease (AD) is a serious neurodegenerative disorder that results in cognitive deterioration, amnesia, and alterations in behavior, rendering it a significant issue in public health. The pathogenesis involves amyloid plaques highlighting the importance of targeting BACE1. This study explores fluspirilene, a di‐phenyl‐butyl‐piperidine as a potential BACE1 inhibitor for AD treatment. Fluspirilene was analyzed for ADMET. In silico molecular docking assessed fluspirilene's binding affinity with BACE1. Re‐docking a co‐crystallized ligand confirmed the docking process. Molecular dynamics simulations and related multifaceted computational analyses were conducted to assess the stability of docked complexes. Fluspirilene had good physicochemical and pharmacokinetic characteristics according to ADMET profiling. In silico molecular docking showed multiple BACE1 interactions with a binding affinity of −9.2 kcal/mol and fluspirilene–BACE1 complex stability was confirmed by molecular dynamics simulation results. Possible therapeutic applications in lowering Aβ generation and treating AD are indicated by the compound's pharmacokinetics, molecular interactions, and binding energetics. Validation and optimization of experiments are necessary for the clinical development of fluspirilene as a BACE1 inhibitor for AD.

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“…Default values were accepted for van der Waals scaling a partial input charges were used. Extra precision docking was used for docking accuracy, and standard precision docking runs for performance indices and enrichment studies, with default settings for all other parameters and no constraints or similarity scoring were applied 39,41 .…”

Section: Generation Of Receptor Grid and Molecular Dockingmentioning

confidence: 99%

Untitled

2019

IJPSR

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In this study, 36 crystal structures available with type I-V inhibitors of VEGFR-2 kinase in the RCSB PDB were classified into DFG-in/-out conformation using visual analysis and KLIFS database. The focus was on Type II inhibitors as most kinase inhibitors belong to this category. Therefore, the crystal structures with DFG-out confirmation with a type II inhibitor were selected depending on the resolution and rfree value. 11 selected crystal structures were subjected to self-docking studies and interaction analysis, leading to the elimination of one crystal structure viz. PDB id 3U6J. 10 crystal structures were subjected to crossdocking analysis. No crystal structures were eliminated at this stage as 50% ligands were docked accurately at RMSD cut off ≤ 2Å. These structures were further evaluated for screening performance by calculation of five performance indicating terms. A rank order was established by performance terms. The next stage of selection was the calculation of enrichment factor and assessment of the number of chemical classes retrieved after docking of the DUD set along with actives. Considering the EF values and the rank order of performance terms; 5 crystal structures were eliminated. Lastly, advanced enrichment parameters such as ROC, AUC, RIE, the average number of outranked decoys, and BEDROC were calculated for the remaining 5 structures. After considering all the stages of evaluation, 4ASE was identified as the most suitable crystal structure. QUICK RESPONSE CODE

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Pharmacophore and Docking Guided Virtual Screening Study for Discovery of Type I Inhibitors of VEGFR-2 Kinase

Abstract: Twelve hits with best obtained docking scores ranging from -10.48 to -7.23 kcal/mol and mimicking characteristic type I inhibitor interactions were identified which could be probable inhibitors of VEGFR-2.

Cited by 12 publications

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Studies in molecular modeling, in-vitro CDK2 inhibition and antimetastatic activity of some synthetic flavones

Studies in molecular modeling, in-vitro CDK2 inhibition and antimetastatic activity of some synthetic flavones

Molecular Dynamics and Binding Energetics of Fluspirilene With BACE1: Implications for Alzheimer's Disease Intervention

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