Molecular dynamics simulation studies on influenza A virus H5N1 complexed with sialic acid and fluorinated sialic acid.
22 Feb 2019-Journal of Biomolecular Structure & Dynamics (Taylor & Francis)-Vol. 37, Iss: 18, pp 4813-4824
TL;DR: AbbreviationsHA HemagglutininMD Molecular DynamicsMM-PBSA Molecular Mechanics Poisson–Boltzmann Surface AreaNA NeuraminidaseNAMD Nanoscale Molecular Dynamic SimulationPMEMD Particle Mesh Ewald Molecular DynamicsRMSD Root-Mean-Square DeviationRMSF Root- mean-square FluctuationSIA sialic acidVMD Visual Molecular Dynamics
Abstract: HAHemagglutininMDMolecular DynamicsMM-PBSAMolecular Mechanics Poisson–Boltzmann Surface AreaNANeuraminidaseNAMDNanoscale Molecular Dynamic SimulationPMEMDParticle Mesh Ewald Molecular DynamicsRMSDR...
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Cites background or methods or result from "Molecular dynamics simulation studi..."
...In our earlier studies on the 50 ns MD simulation of H5N1 Influenza A virus complexed with SIA and mono fluorinated SIA concludes that the fluorine substitution at O2, O7 and O9 hydroxyl positions of SIA enhance the inhibiting potency against H5N1 Influenza A virus (Jeyaram et al., 2019)....
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...Both RMSD and RMSF measurements are similar to our earlier report (Jeyaram et al., 2019)....
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...In our earlier report (Jeyaram et al., 2019), we indicated that the water involved in the mediated hydrogen bonds are considered as Figure 2....
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...In our earlier studies on the 50 ns MD simulation of H5N1 Influenza A virus complexed with SIA and mono fluorinated SIA concludes that the fluorine substitution at O2, O7 and O9 hydroxyl positions of SIA enhance the inhibiting potency against H5N1 Influenza A virus (Jeyaram et al., 2019)....
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...…between H5 active site residues and the fluorinated SIA (except H5 – SIA-F2F7) are similar to the parent H5 – SIA complex reported in our earlier study (Jeyaram et al., 2019) and Yang, Li, Shen, and Liu (2013) reported that the MD simulation of H5 active site residues in 130-loop and 190-helix are…...
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TL;DR: In this article , a combination of LESMD simulations for 10 TSC conformations with a p53R175H receptor, single ligand-protein conformation MD, and ensemble docking with multiple p53 R175H conformations observed during simulations is suggested to identify the potential binding site of the target protein in light of their importance for the direct TSC binding.
Abstract: Cancer pathologies are associated with the unfolding and aggregation of most recurring mutations in the DNA Binding Domain (DBD) of p53 that coordinate the destabilization of protein. Substitution at the 175th codon with arginine to histidine (R175H, a mutation of large to small side-chain amino acid) destabilizes the DBD by 3 kcal/mol and triggers breasts, lung cancer, etc. Stabilizing the p53 mutant by small molecules offers an attractive drug-targeted anti-cancer therapy. The thiosemicarbazone (TSC) molecules NPC and DPT are known to act as zinc-metallochaperones to reactivate p53R175H. Here, a combination of LESMD simulations for 10 TSC conformations with a p53R175H receptor, single ligand-protein conformation MD, and ensemble docking with multiple p53R175H conformations observed during simulations is suggested to identify the potential binding site of the target protein in light of their importance for the direct TSC – p53R175H binding. NPC binds mutant R175H in the loop region L2-L3, forming pivotal hydrogen bonds with HIS175, pi‑sulfur bonds with TYR163, and pi-alkyl linkages with ARG174 and PRO190, all of which are contiguous to the zinc-binding native site on p53DBD. DPT, on the other hand, was primarily targeting alternative binding sites such as the loop-helix L1/H2 region and the S8 strand. The similar structural characteristics of TSC-bound p53R175H complexes with wild-type p53DBD are thought to be attributable to involved interactions that favour binding free energy contributions of TSC ligands. Our findings may be useful in the identification of novel pockets with druggable properties.
References
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TL;DR: AutoDock4 incorporates limited flexibility in the receptor and its utility in analysis of covalently bound ligands is reported, using both a grid‐based docking method and a modification of the flexible sidechain technique.
Abstract: We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.
15,616 citations
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...(Morris et al., 2009) software is used for molecular docking....
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TL;DR: The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development, and a major challenge moving forward will be how and where to install fluorine to best optimise molecular properties.
Abstract: The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.
491 citations
"Molecular dynamics simulation studi..." refers background in this paper
...Shah & Westwell (2007) CONTACT K. Veluraja veluraja.k@vit.ac.in; kvrajamsu@gmail.com Supplemental data for this article can be accessed online at https://doi.org/10.1080/07391102.2019.1568304....
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TL;DR: The fatal case of a patient in China who was infected with an A(H7N9) virus having a polybasic amino acid sequence at its hemagglutinin cleavage site (PEVPKRKRTAR/GL), a sequence suggestive of high pathogenicity in birds, is reported.
Abstract: The recent increase in zoonotic avian influenza A(H7N9) disease in China is a cause of public health concern. Most of the A(H7N9) viruses previously reported have been of low pathogenicity. We report the fatal case of a patient in China who was infected with an A(H7N9) virus having a polybasic amino acid sequence at its hemagglutinin cleavage site (PEVPKRKRTAR/GL), a sequence suggestive of high pathogenicity in birds. Its neuraminidase also had R292K, an amino acid change known to be associated with neuraminidase inhibitor resistance. Both of these molecular features might have contributed to the patient's adverse clinical outcome. The patient had a history of exposure to sick and dying poultry, and his close contacts had no evidence of A(H7N9) disease, suggesting human-to-human transmission did not occur. Enhanced surveillance is needed to determine whether this highly pathogenic avian influenza A(H7N9) virus will continue to spread.
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...The first case of human infection with H5N1 occurred at Hong Kong in 1997, and in 2013 human infection with H7N9 was reported in China (Ke et al., 2017)....
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TL;DR: It is demonstrated that cattle experimentally infected with IDV can shed virus and transmit it to other cattle through direct contact, but not to ferrets through fomite routes, supporting the hypothesis that cattle are a natural reservoir for the virus.
Abstract: Cattle have been proposed as the natural reservoir of a novel member of the virus family Orthomyxoviridae, which has been tentatively classified as influenza D virus (IDV). Although isolated from sick animals, it is unclear whether IDV causes any clinical disease in cattle. To address this aspect of Koch9s postulates, three dairy calves (treatment animals) held in individual pens were inoculated intranasally with IDV strain D/bovine/Mississippi/C00046N/2014. At 1 day postinoculation, a seronegative calf (contact animal) was added to each of the treatment animal pens. The cattle in both treatment and contact groups seroconverted, and virus was detected in their respiratory tracts. Histologically, there was a significant increase in neutrophil tracking in tracheal epithelia of the treatment calves compared to control animals. While infected and contact animals demonstrated various symptoms of respiratory tract infection, they were mild, and the calves in the treatment group did not differ from the controls in terms of heart rate, respiratory rate, or rectal temperature. To mimic zoonotic transmission, two ferrets were exposed to a plastic toy fomite soaked with infected nasal discharge from the treatment calves. These ferrets did not shed the virus or seroconvert. In summary, this study demonstrates that IDV causes a mild respiratory disease upon experimental infection of cattle and can be transmitted effectively among cattle by in-pen contact, but not from cattle to ferrets through fomite exposure. These findings support the hypothesis that cattle are a natural reservoir for the virus. IMPORTANCE A novel influenza virus, tentatively classified as influenza D virus (IDV), was identified in swine, cattle, sheep, and goats. Among these hosts, cattle have been proposed as the natural reservoir. In this study, we show that cattle experimentally infected with IDV can shed virus and transmit it to other cattle through direct contact, but not to ferrets through fomite routes. IDV caused minor clinical signs in the infected cattle, fulfilling another of Koch9s postulates for this novel agent, although other objective clinical endpoints were not different from those of control animals. Although the disease observed was mild, IDV induced neutrophil tracking and epithelial attenuation in cattle trachea, which could facilitate coinfection with other pathogens, and in doing so, predispose animals to bovine respiratory disease.
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...Influenza D virus infects cattle, and there is no evidence of human infection (Ferguson et al., 2016)....
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TL;DR: The present study is clear, consistent and could give a rational explanation for the binding mode of the best selected ligand, which might be functional to this worldwide disease.
Abstract: In March and April, 2009, an outbreak of H1N1 influenza in Mexico had led to hundreds of confirmed cases and the death toll had risen to 160. The worldwide spread of H1N1 has been attracting global attention and arising an overwhelming fear. So far, the vaccine and remedy has been in urgent need. In this study, a QSAR model and pharmacophore map of neuraminidase (NA) type 1 (N1) contained two hydrogen bond acceptor features, one hydrogen bond donor feature, and one positive ionizable feature. NCI database was employed in virtual screen by the N1 pharmacophore map features. After screening, compounds were obtained and then docked into haemagglutinin type 1 (H1) to find out the candidate drugs for dual target of both N1 and H1. The candidate, NCI0353858, selected via virtual screening and docking, might be functional to this worldwide disease; consequently, further clinical investigations and scientific application are urgently demanded. We realize the proposed ligand does not have much validity without conducting a study on the stability of the protein-ligand complex by MD simulations and binding free energy, and such a study is underway and will be reported later in this journal. Nevertheless, the present study is clear, consistent and could give a rational explanation for the binding mode of the best selected ligand.
84 citations