Investigation of novel chemical scaffolds targeting prolyl oligopeptidase for neurological therapeutics

Kumar, Raj; Saravanan, P.; Bavi, Rohit; Baek, Ayoung; Son, Maeng-Hyun; Rampogu, Shailima; Park, Chanin; Lee, Gihwan; Zeb, Amir; Parate, Shraddha; Rana, Rabia Mukhtar; Lee, Keun Woo

doi:10.1016/j.jmgm.2018.12.006

Cited by 10 publications

(5 citation statements)

References 47 publications

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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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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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“…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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“…Molecular mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) was used to compute the binding free energy as described previously (Bavi et al., 2016 , 2017 ; Kumar et al., 2019 ). For computing binding free energy, 30 snapshots of protein-ligand complex were chosen evenly from 0 to 30 ns of molecular dynamics simulation trajectories as per the previous studies (Bavi et al., 2019 ; Hou et al., 2011 ).…”

Section: Methodsmentioning

confidence: 99%

Identification and characterization of novel RdRp and Nsp15 inhibitors for SARS-COV2 using computational approach

Barage

Karthic

Bavi

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The World Health Organization has declared COVID-19 as a global health emergency. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and highlights an urgent need for therapeutics. Here, we have employed a series of computer-aided drug repurposing campaign to discover inhibitors of RNA dependent RNA polymerase (RdRp) and Nsp15/EndoU. Subsequently, MD simulation has been performed to observe dynamic behavior of identified leads at the active site of RdRp and Nsp15. We successfully identified novel lead molecule such as Alectinib for RdRp while Naldemedine and Ergotamine for NSP15. These lead molecules were accommodated in the active site of the enzyme and stabilized by the networks of the hydrogen bond, pi type and hydrophobic interaction with key residues of either target. Interestingly, identified compounds show molecular mimicry in terms of molecular interactions with key residues of RdRp and Nsp15 essential for catalysis and substrate interaction. Previously, Alectinib, Naldemedine and Ergotamine were used as drug in different diseases might be repurposed against selected protein targets of COVID19. Finally, we propose that the identified inhibitors represent a novel lead molecule to design a more effective inhibitor to stop the progress of pathogen. Communicated by Ramaswamy H. Sarma

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Investigation of novel chemical scaffolds targeting prolyl oligopeptidase for neurological therapeutics

Cited by 10 publications

References 47 publications

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

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

Identification and characterization of novel RdRp and Nsp15 inhibitors for SARS-COV2 using computational approach

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