Conformational Characterization of Linker Revealed the Mechanism of Cavity Formation by 227G in BVDV RDRP

Mittal, Lovika; Srivastava, Mitul; Asthana, Shailendra

doi:10.1021/acs.jpcb.9b01859

Cited by 27 publications

(29 citation statements)

References 37 publications

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“…All the images were generated using VMD and Schrodinger Suite (Asthana et al, 2014(Asthana et al, , 2015Humphrey et al, 1996) and graphs were plotted using XMGRACE (Mittal et al, 2019;Turner, 2005).…”

Section: Figuresmentioning

confidence: 99%

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Mittal

Kumari

Srivastava

et al. 2020

Journal of Biomolecular Structure and Dynamics

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162

103

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The pandemic caused by novel coronavirus disease 2019 infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (M pro ) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of M pro was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of M pro . However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with hot-spot residues, that are mainly conserved and can be targeted for structure-and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for in-vitro studies. ARTICLE HISTORY

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Section: Figuresmentioning

confidence: 99%

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Mittal

Kumari

Srivastava

et al. 2020

Journal of Biomolecular Structure and Dynamics

Self Cite

162

103

View full text Add to dashboard Cite

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“…The capsid dimer was generated through homology modelling. The structures were optimized and then minimized using the Protein Preparation Wizard module of Maestro (Schrödinger Release 2020–1: Maestro, Schrödinger, LLC, New York, NY, 2020) [58, 59]. Since the complete active form models of capsid and LC3 are not available, homology models were generated through the modeller [60] to understand the complete structures.…”

Section: Methodsmentioning

confidence: 99%

“…Molecular dynamics minimization was employed to allow conformational relaxation of the protein structures prior to subjecting them to protein-protein docking calculations [59]. Subsequently, two different algorithms (PyDOCK and Swarmdock) were used to perform the protein-protein dockings to identify the most likely binding interfaces and poses of capsid-LC3 interactions.…”

Section: Protein-protein Docking Studymentioning

confidence: 99%

Japanese encephalitis virus capsid protein interacts with non-lipidated MAP1LC3 on replication membranes and lipid droplets

Sarkar

Sharma

Kumari

et al. 2021

Journal of General Virology

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Microtubule-associated protein 1 light chain 3 (MAP1LC3) is a protein with a well-defined function in autophagy, but still incompletely understood roles in several other autophagy-independent processess. Studies have shown MAP1LC3 is a host-dependency factor for the replication of several viruses. Japanese encephalitis virus (JEV), a neurotropic flavivirus, replicates on ER-derived membranes that are marked by autophagosome-negative non-lipidated MAP1LC3 (LC3-I). Depletion of LC3 exerts a profound inhibition on virus replication and egress. Here, we further characterize the role of LC3 in JEV replication, and through immunofluorescence and immunoprecipitation show that LC3-I interacts with the virus capsid protein in infected cells. This association was observed on capsid localized to both the replication complex and lipid droplets (LDs). JEV infection decreased the number of LDs per cell indicating a link between lipid metabolism and virus replication. This capsid-LC3 interaction was independent of the autophagy adaptor protein p62/Sequestosome 1 (SQSTM1). Further, no association of capsid was seen with the Gamma-aminobutyric acid receptor-associated protein family, suggesting that this interaction was specific for LC3. High-resolution protein-protein docking studies identified a putative LC3-interacting region in capsid, 56FTAL59, and other key residues that could mediate a direct interaction between the two proteins.

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“…In the current scenario the cornerstone of modern medicinal chemistry is ligand- and Structure-based drug discovery (LB/SBDD) which has inspired numerous small molecule lead optimization efforts and play a role in the discovery of drugs and drug like molecules immensely 20 , 21 . The protein structures have increased exponentially and now confine highly dynamic targets also which was previously impervious to crystallography.…”

Section: Structural Architecture At Atomic Level and Elucidation Of Pmentioning

confidence: 99%

Bile acids mediated potential functional interaction between FXR and FATP5 in the regulation of Lipid Metabolism

2020

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Perturbation in lipid homeostasis is one of the major bottlenecks in metabolic diseases, especially Non-alcoholic Fatty Liver Disease (NAFLD), which has emerged as a leading global cause of chronic liver disease. The bile acids (BAs) and their derivatives exert a variety of metabolic effects through complex and intertwined pathways, thus becoming the attractive target for metabolic syndrome treatment. To modulate the lipid homeostasis, the role of BAs, turn out to be paramount as it is essential for the absorption, transport of dietary lipids, regulation of metabolic enzymes and transporters that are essential for lipid modulation, flux, and excretion. The synthesis and transport of BAs (conjugated and unconjugated) is chiefly controlled by nuclear receptors and the uptake of long-chain fatty acids (LCFA) and BA conjugation via transporters. Among them, from in-vivo studies, farnesoid X receptor (FXR) and liver-specific fatty acid transport protein 5 (FATP5) have shown convincing evidence for their key roles in lipid homeostasis and reversal of fatty liver disease substantially. BAs have a wider range of biological effects as they are identified as modulators for FXR and FATP5 both and therefore hold a significant promise for altering the lipid content in the treatment of a metabolic disorder. BAs also have received noteworthy interest in drug delivery research due to its peculiar physicochemical properties and biocompatibility. Here, we are highlighting the connecting possibility of BAs as an agonist for FXR and antagonist for FATP5, paving an avenue to target them for designing synthetic small molecules for lipid homeostasis.

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Conformational Characterization of Linker Revealed the Mechanism of Cavity Formation by 227G in BVDV RDRP

Cited by 27 publications

References 37 publications

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Japanese encephalitis virus capsid protein interacts with non-lipidated MAP1LC3 on replication membranes and lipid droplets

Bile acids mediated potential functional interaction between FXR and FATP5 in the regulation of Lipid Metabolism

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