YASARA: A Tool to Obtain Structural Guidance in Biocatalytic Investigations

Land, Henrik; Humble, Maria Svedendahl

doi:10.1007/978-1-4939-7366-8_4

Cited by 376 publications

(298 citation statements)

References 31 publications

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“…The DPP4 protein structure (4PV7) [43] and the structure of the complex formed by the MERS-CoV S receptor binding domain bound to DPP4 (4L72) [16] were retrieved from the Research Collaboratory for Structural Bioinformatics Protein Database (RSCB PDB, https://www.rcsb.org/). Structure visualization and colorization was performed using the YASARA software (http://www.yasara.org/index.html) [44] and UCSF Chimera version 1.14 (developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco) [45].…”

Section: Protein Structure Visualizationmentioning

confidence: 99%

Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus

Kleine-Weber

Schroeder

Krüger

et al. 2020

Emerging Microbes & Infections

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Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) causes a severe respiratory disease in humans. The MERS-CoV spike (S) glycoprotein mediates viral entry into target cells. For this, MERS-CoV S engages the host cell protein dipeptidyl peptidase 4 (DPP4, CD26) and the interface between MERS-CoV S and DPP4 has been resolved on the atomic level. Here, we asked whether naturally-occurring polymorphisms in DPP4, that alter amino acid residues required for MERS-CoV S binding, influence cellular entry of MERS-CoV. By screening of public databases, we identified fourteen such polymorphisms. Introduction of the respective mutations into DPP4 revealed that all except one (Δ346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients.

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Section: Protein Structure Visualizationmentioning

confidence: 99%

Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus

Kleine-Weber

Schroeder

Krüger

et al. 2020

Emerging Microbes & Infections

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“…Lanosterol 14α-demethylase (LDM) from F. cerealis was selected as test enzyme for 90-ns molecular dynamics simulations due to its better molecular docking behavior with the test phytoalexin analogs, specifically compound 24. The 3D structure of this enzyme was built through homology modeling using Yasara Structure [26], since no crystal data is available, embedded in a 266-lipids OPPEA bilayer. This simulation was implemented as the next step to expand the information about the binding mode of this promising candidate.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…These structures were 3D-sketched and organized according to close-related moieties affording seven substituted groups such as 2-alkyl aminoesters (1-4), N,N-dialkylthioureas (5-8), 2-cyanoethyl N-alkyldithiocarbamates (9-12), 3-methoxy-3-oxopropyl N-alkyldithiocarbamate (13-16), 2-methyl-4-oxopentan-2-yl N-alkyldithiocarbamate (17)(18)(19)(20), 2-oxo-1,3-diphenylpropyl N-alkyldithiocarbamates (21-24) and 4-[(1H-indol-3-yl)-methylene]-2-sulfanylidene-1,3-thiazolidin-5-one (25). Brassinin (26) was included into the study and used as reference compound. A previous MMFF geometry minimization for each ligand was carried out in Spartan'14 (Wavefunction, Irvine, CA, USA) without any geometrical restrictions, prior to the docking and dynamics simulations.…”

Section: Design and Synthesis Of Indole-containing Phytoalexin Analogsmentioning

confidence: 99%

Indole-Containing Phytoalexin-Based Bioisosteres as Antifungals: In Vitro and In Silico Evaluation against Fusarium oxysporum

2019

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There is a continuous search for more reliable and effective alternatives to control phytopathogens through different strategies. In this context, indole-containing phytoalexins are stimuli-induced compounds implicated in plant defense against plant pathogens. However, phytoalexins' efficacy have been limited by fungal detoxifying mechanisms, thus, the research on bioisosteres-based analogs can be a friendly alternative regarding the control of Fusarium phytopathogens, but there are currently few studies on it. Thus, as part of our research on antifungal agents, a set of 21 synthetic indole-containing phytoalexin analogs were evaluated as inhibitors against the phyopathogen Fusarium oxysporum. Results indicated that analogs of the N,N-dialkylthiourea, N,S-dialkyldithiocarbamate and substituted-1,3-thiazolidin-5-one groups exhibited the best docking scores and interaction profiles within the active site of Fusarium spp. enzymes. Vina scores exhibited correlation with experimental mycelial growth inhibition using supervised statistics, and this antifungal dataset correlated with molecular interaction fields after CoMFA. Compound 24 (tert-butyl (((3-oxo-1,3-diphenylpropyl)thio)carbonothioyl)-l-tryptophanate), a very active analog against F. oxysporum, exhibited the best interaction with lanosterol 14α-demethylase according to molecular docking, molecular dynamics and molecular mechanic/poisson-boltzmann surface area (MM/PBSA) binding energy performance. After data analyses, information on mycelial growth inhibitors, structural requirements and putative enzyme targets may be used in further antifungal development based on phytoalexin analogs for controlling phytopathogens.Molecules 2020, 25, 45 2 of 19 fungal toxins [2]. In this context, some control strategies based on chemical, physical and cultural methods have arisen to mitigate the negative effects of this phytopathogen to host plants. Chemical treatments include formaldehyde applications to avoid disseminations as well as dazomet, sodium methan, methyl isothiocyanate and systemic fungicides as benomyl, thiabendazon, carbendazim and methylthiophanate [3]. Fusarium-caused diseases treatment by systemic fungicides, although it has good effectivity, is also problematic, since these kind of treatments can become mutagenics for several plants and these agents can also generate high degrees of resistance [3,4].Plants involve a systemic defense mechanism involving some metabolites such as phytoalexins. These metabolites are synthesized in adjacent areas of healthy cells to those damaged cells and they are accumulated both in necrotic and susceptible resistant tissues [5]. In other words, they are strictly produced in a site around the place where infection needs to be controlled. Thus, the resistance occurs when one or more phytoalexins reach a high enough concentration to inhibit the pathogen development [5]. However, some phytopathogens are recently described to exhibit strategies to invade the plant tissues and obtain necessary nutrients for its growing and reproduc...

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“…PDB coordinate files were then used in downstream analysis. Energy minimization of the 3D structures was performed using YASARA Structure, which runs molecular dynamics simulations of models in explicit solvent, using a new partly knowledge-based all atom force field derived from the force field Amber99SB (Land and Humble, 2018).…”

Section: Homology Modelingmentioning

confidence: 99%

Molecular dynamics suggests antiviral compounds active against Dengue Virus show similar binding patterns to Zika Virus proteins

Neto

Soares

Pour

et al. 2018

Preprint

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The Zika virus (ZIKV) arrival in Brazilian territory brought to light the need for preparedness regarding arboviruses in Brazil. Compound screening is a cumbersome process dependent upon in vitro testing and validation. Recently, virtual screening methods have improved precision and reliability providing a framework for in silico testing of lead compound candidates. Here we have applied these methods on compounds that were previously shown to be active against Dengue virus in vitro, taking the structural information of such compounds and applying docking methods to identify putative binding sites. A molecular dynamics approach was also used to refine the docking results. The computational experiments ran here suggests that compounds such as Epigallocatechin Gallate, Ergotamine and Avermectin-B1a bind to active sites on the viral enzymes NS5 and NS3, as well as on its Envelope protein. Refinement shows that such bindings were not lost during the production run and key regions on both enzymes were structurally displaced on average over the simulation time. Interestingly there is no documented drug interactions among these candidates, raising the possibility of drug combinations during treatments.Moreover, the candidate compounds have been extensively studied, thus providing important information regarding intracellular interactions caused by them, which are also associated with pathways exploited by the virus, suggesting possible side interactions hindering the replication process.

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YASARA: A Tool to Obtain Structural Guidance in Biocatalytic Investigations

Cited by 376 publications

References 31 publications

Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus

Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus

Indole-Containing Phytoalexin-Based Bioisosteres as Antifungals: In Vitro and In Silico Evaluation against Fusarium oxysporum

Molecular dynamics suggests antiviral compounds active against Dengue Virus show similar binding patterns to Zika Virus proteins

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