Novel virtual lead identification in the discovery of hematopoietic cell kinase (HCK) inhibitors: application of 3D QSAR and molecular dynamics simulation

Bavi, Rohit; Kumar, Raj; Rampogu, Shailima; Kim, Yong-Seong; Kwon, Yong Jung; Park, Seok Ju; Lee, Keun Woo

doi:10.1080/10799893.2016.1212376

Cited by 10 publications

(7 citation statements)

References 49 publications

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“…The molecular dynamics (MD) simulations of POP in a complex with inhibitors and final hit compounds were carried out with CHARMM27 all-atom force field using Groningen machine for chemical simulations (GROMACS 4.5.7) software 55 , as previously described 56 – 58 . The topology files for all ligands were generated using the SwissParam program 59 .…”

Section: Methodsmentioning

confidence: 99%

New compounds identified through in silico approaches reduce the α-synuclein expression by inhibiting prolyl oligopeptidase in vitro

Kumar¹,

Bavi²,

Jo³

et al. 2017

Sci Rep

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Prolyl oligopeptidase (POP) is a serine protease that is responsible for the maturation and degradation of short neuropeptides and peptide hormones. The inhibition of POP has been demonstrated in the treatment of α-synucleinopathies and several neurological conditions. Therefore, ligand-based and structure-based pharmacophore models were generated and validated in order to identify potent POP inhibitors. Pharmacophore-based and docking-based virtual screening of a drug-like database resulted in 20 compounds. The in vitro POP assays indicated that the top scoring compounds obtained from virtual screening, Hit 1 and Hit 2 inhibit POP activity at a wide range of concentrations from 0.1 to 10 µM. Moreover, treatment of the hit compounds significantly reduced the α-synuclein expression in SH-SY5Y human neuroblastoma cells, that is implicated in Parkinson’s disease. Binding modes of Hit 1 and Hit 2 compounds were explored through molecular dynamics simulations. A detailed investigation of the binding interactions revealed that the hit compounds exhibited hydrogen bond interactions with important active site residues and greater electrostatic and hydrophobic interactions compared to those of the reference inhibitors. Finally, our findings indicated the potential of the identified compounds for the treatment of synucleinopathies and CNS related disorders.

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Section: Methodsmentioning

confidence: 99%

New compounds identified through in silico approaches reduce the α-synuclein expression by inhibiting prolyl oligopeptidase in vitro

Kumar¹,

Bavi²,

Jo³

et al. 2017

Sci Rep

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“…Based on the RMSD plots, last 10 ns simulation trajectories were selected and a total of 40 snapshots were taken at a regular interval. The g_mmpbsa tool for GROMACS was employed to calculate the different parameters of binding free energies with the methodologies described in previous reports [46][47][48][49] .…”

Section: Binding Free Energy Calculationsmentioning

confidence: 99%

Insilico drug repurposing using FDA approved drugs against Membrane protein of SARS-CoV-2

Peele

Kumar

Parate

et al. 2021

Journal of Pharmaceutical Sciences

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…The binding free energy calculation study was useful in calculating the binding potential of hexanucleotides because it offers a quantitative estimation of the binding free energy. 30 , 31 , 32 , 33 , 34 The MM-PBSA method was used to calculate the binding free energy of the selected hexanucleotides to their protein. The calculations were performed by extracting the trajectories from the last 5 ns when the system was well-equilibrated.…”

Section: Resultsmentioning

confidence: 99%

Doxorubicin-Conjugated Innovative 16-mer DNA Aptamer-Based Annexin A1 Targeted Anti-Cancer Drug Delivery

Bavi

Hang

Banerjee

et al. 2020

Molecular Therapy - Nucleic Acids

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Aptamers are small, functional single-stranded DNA or RNA oligonucleotides that bind to their targets with high affinity and specificity. Experimentally, aptamers are selected by the systematic evolution of ligands by exponential enrichment (SELEX) method. Here, we have used rational drug designing and bioinformatics methods to design the aptamers, which involves three different steps. First, finding a probable aptamer-binding site, and second, designing the recognition and structural parts of the aptamers by generating a virtual library of sequences, selection of specific sequence via molecular docking, molecular dynamics (MD) simulation, binding energy calculations, and finally evaluating the experimental affinity. Following this strategy, a 16-mer DNA aptamer was designed for Annexin A1 (ANXA1). In a direct binding assay, DNA1 aptamer bound to the ANXA1 with dissociation constants value of 83 nM. Flow cytometry and fluorescence microscopy results also showed that DNA1 aptamer binds specifically to A549, HepG2, U-87 MG cancer cells that overexpress ANXA1 protein, but not to MCF7 and L-02, which are ANXA1 negative cells. We further developed a novel system by conjugating DNA1 aptamer with doxorubicin and its efficacy was studied by cellular uptake and cell viability assay. Also, anti-tumor analysis showed that conjugation of doxorubicin with aptamer significantly enhances targeted therapy against tumors while minimizing overall adverse effects on mice health.

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Novel virtual lead identification in the discovery of hematopoietic cell kinase (HCK) inhibitors: application of 3D QSAR and molecular dynamics simulation

Cited by 10 publications

References 49 publications

New compounds identified through in silico approaches reduce the α-synuclein expression by inhibiting prolyl oligopeptidase in vitro

New compounds identified through in silico approaches reduce the α-synuclein expression by inhibiting prolyl oligopeptidase in vitro

Insilico drug repurposing using FDA approved drugs against Membrane protein of SARS-CoV-2

Doxorubicin-Conjugated Innovative 16-mer DNA Aptamer-Based Annexin A1 Targeted Anti-Cancer Drug Delivery

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