13 results on '"Nazaryan, Karen"'
Search Results
2. Combination of consensus and ensemble docking strategies for the discovery of human dihydroorotate dehydrogenase inhibitors
- Author
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Chilingaryan, Garri, Abelyan, Narek, Sargsyan, Arsen, Nazaryan, Karen, Serobian, Andre, and Zakaryan, Hovakim
- Published
- 2021
- Full Text
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3. Identification of non-classical hCA XII inhibitors using combination of computational approaches for drug design and discovery
- Author
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Al-Sanea, Mohammad M., Chilingaryan, Garri, Abelyan, Narek, Arakelov, Grigor, Sahakyan, Harutyun, Arakelov, Vahram G., Nazaryan, Karen, Hussein, Shaimaa, Alazmi, Gharam M., Alsharari, Haifa E., Al-faraj, Waad M., Alruwaili, Faten S., Albilasi, Nouf Q., Alsharari, Tahani S., Alsaleh, Abdulaziz A. S., Alazmi, Turki M., Almalki, Atiah H., Alotaibi, Nasser H., and Abdelgawad, Mohamed A.
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- 2021
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4. Effect of Colchicine Binding Site Inhibitors on the Tubulin Intersubunit Interaction.
- Author
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Sargsyan, Arsen, Sahakyan, Harutyun, and Nazaryan, Karen
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- 2023
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5. A Study of a Protein-Folding Machine: Transient Rotation of the Polypeptide Backbone Facilitates Rapid Folding of Protein Domains in All-Atom Molecular Dynamics Simulations.
- Author
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Sahakyan, Harutyun, Nazaryan, Karen, Mushegian, Arcady, and Sorokina, Irina
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MOLECULAR dynamics , *PROTEIN domains , *PROTEIN folding , *SPINE , *PEPTIDES - Abstract
Molecular dynamics simulations of protein folding typically consider the polypeptide chain at equilibrium and in isolation from the cellular components. We argue that in order to understand protein folding as it occurs in vivo, it should be modeled as an active, energy-dependent process, in which the cellular protein-folding machine directly manipulates the polypeptide. We conducted all-atom molecular dynamics simulations of four protein domains, whose folding from the extended state was augmented by the application of rotational force to the C-terminal amino acid, while the movement of the N-terminal amino acid was restrained. We have shown earlier that such a simple manipulation of peptide backbone facilitated the formation of native structures in diverse α-helical peptides. In this study, the simulation protocol was modified, to apply the backbone rotation and movement restriction only for a short time at the start of simulation. This transient application of a mechanical force to the peptide is sufficient to accelerate, by at least an order of magnitude, the folding of four protein domains from different structural classes to their native or native-like conformations. Our in silico experiments show that a compact stable fold may be attained more readily when the motions of the polypeptide are biased by external forces and constraints. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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6. A new microtubule-stabilizing agent shows potent antiviral effects against African swine fever virus with no cytotoxicity.
- Author
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Sirakanyan, Samvel, Arabyan, Erik, Hakobyan, Astghik, Hakobyan, Tamara, Chilingaryan, Garri, Sahakyan, Harutyun, Sargsyan, Arsen, Arakelov, Grigor, Nazaryan, Karen, Izmailyan, Roza, Abroyan, Liana, Karalyan, Zaven, Arakelova, Elina, Hakobyan, Elmira, Hovakimyan, Anush, Serobian, Andre, Neves, Marco, Ferreira, João, Ferreira, Fernando, and Zakaryan, Hovakim
- Published
- 2021
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7. In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism.
- Author
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Sahakyan, Harutyun, Abelyan, Narek, Arakelov, Vahram, Arakelov, Grigor, and Nazaryan, Karen
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TUBULINS ,FAMILIAL Mediterranean fever ,BINDING energy ,MOLECULAR dynamics ,AMINO acids ,SOLID state physics - Abstract
Starting from 1972, colchicine is known as the most useful drug for prevention of familial Mediterranean fever attacks. However, some patients do not respond to colchicine treatment, even taken in high doses. Despite the fact, that different hypotheses have been proposed, the molecular mechanisms of colchicine resistance are not completely clear. It is generally known, that colchicine binds β-tubulin and inhibits microtubules polymerization. The β-tubulin gene has SNPs, which lead to amino acid substitutions, and some of them are located in colchicine binding site (CBS). We have assumed, that this SNPs can affect tubulin-colchicine interaction and might be the reason for colchicine resistance. With this in mind, we modeled 7 amino acid substitutions in CBS, performed molecular dynamics simulations of tubulin-colchicine complex and calculated binding energies for every amino acid substitution. Thus, our study shows, that two amino acid substitutions in the β-tubulin, namely A248T and M257V, reduce binding energy for approximately 2-fold. Based on this, we assume, that these amino acid substitutions could be the reason for colchicine resistance. Thus, our study gives a new insight into colchicine resistance mechanism and provides information for designing colchicine alternatives, that could be effective for colchicine resistant patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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8. Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase‐1.
- Author
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Arakelov, Grigor, Arakelov, Vahram, and Nazaryan, Karen
- Abstract
Abstract: Pyrin protein is the product of the MEFV gene, mutations in which cause manifestation of familial Mediterranean fever (FMF). Functions of pyrin are not completely clear. The secondary structure of the pyrin is represented with four domains and two motifs. Mutations p.M680I, p.M694V, p.M694I, p.K695R, p.V726A, and p.A744S, which are located in the B30.2 domain of pyrin protein, are responsible for manifestation of the most common and severe forms of FMF. All the domains and the motifs of pyrin, are directly or indirectly, involved in the protein–protein interaction with proteins of apoptosis and regulate the cascade of inflammatory reactions, which is impaired due to pyrin mutations. It is well known, that malfunction of the pyrin‐caspase‐1 complex is the main reason of inflammation during FMF. Complete tertiary structure of pyrin and the effects of mutations in it are experimentally not studied yet. The aim of this study was to identify possible effects of the abovementioned mutations in the B30.2 domain tertiary structure and to determine their potential consequences in formation of the B30.2‐caspase‐1 complex. Using in silico methods, it was found, that these mutations led to structural rearrangements in B30.2 domain tertiary structure, causing shifts of binding sites and altering the interaction energy between B30.2 and caspase‐1. [ABSTRACT FROM AUTHOR]
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- 2018
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9. Molecular dynamics study of interaction and substrate channeling between neuron-specific enolase and B-type phosphoglycerate mutase.
- Author
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Hakobyan, Davit and Nazaryan, Karen
- Abstract
Phosphoglycerate mutase (PGM) and enolase are consecutive enzymes in the glycolytic pathway. We used molecular dynamics simulation to examine the interaction of human B-type PGM (dPGM-B) and neuron-specific enolase (NSE). Specifically, we studied the interactions of 31 orientations of these enzymes by means of the effective energy function implicit solvation method. Interactions between active regions of the enzymes occurred preferentially, although the strongest interactions appeared to be between the back side of NSE and the active regions of dPGM-B. Cleavage of 2PG from dPGM-B was investigated, and the Ser
14 -Leu30 loop of dPGM-B is suggested as a cleavage site and, likely, another entrance site of a ligand. Substrate channeling between the enzymes was observed when NSE with its active regions Leu11 -Asn16 , Arg49 -Lys59 , and Gly155 -Ala158 covered the Ser14 -Leu30 loop of dPGM-B. Analyses of the results make us believe that the channeling between PGM and enolase 'benefits' from weak interaction. The probability of formation of channeling favorable complex is estimated to be up to 5%, while functional interaction between NSE and dPGM-B might be as high as 20%. NSE and dPGM-B functional interaction seems not to be isotype specific. Proteins 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]- Published
- 2010
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10. Mechanism of external K+ sensitivity of KCNQ1 channels.
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Abrahamyan, Astghik, Eldstrom, Jodene, Sahakyan, Harutyun, Karagulyan, Nare, Mkrtchyan, Liana, Karapetyan, Tatev, Sargsyan, Ernest, Kneussel, Matthias, Nazaryan, Karen, Schwarz, Jürgen R., Fedida, David, and Vardanyan, Vitya
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MOLECULAR dynamics , *PHYSIOLOGY , *MUTAGENESIS - Abstract
KCNQ1 voltage-gated K+ channels are involved in a wide variety of fundamental physiological processes and exhibit the unique feature of being markedly inhibited by external K+. Despite the potential role of this regulatory mechanism in distinct physiological and pathological processes, its exact underpinnings are not well understood. In this study, using extensive mutagenesis, molecular dynamics simulations, and single-channel recordings, we delineate the molecular mechanism of KCNQ1 modulation by external K+. First, we demonstrate the involvement of the selectivity filter in the external K+ sensitivity of the channel. Then, we show that external K+ binds to the vacant outermost ion coordination site of the selectivity filter inducing a diminution in the unitary conductance of the channel. The larger reduction in the unitary conductance compared to whole-cell currents suggests an additional modulatory effect of external K+ on the channel. Further, we show that the external K+ sensitivity of the heteromeric KCNQ1/KCNE complexes depends on the type of associated KCNE subunits. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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11. Inhibition of African swine fever virus infection by genkwanin.
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Hakobyan, Astghik, Arabyan, Erik, Kotsinyan, Armen, Karalyan, Zaven, Sahakyan, Harutyun, Arakelov, Vahram, Nazaryan, Karen, Ferreira, Fernando, and Zakaryan, Hovakim
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AFRICAN swine fever , *AFRICAN swine fever virus , *VIRUS diseases , *DNA synthesis , *POLAR solvents , *APIGENIN - Abstract
African swine fever virus (ASFV) is the causative agent of an economically important disease of pigs for which no effective vaccines or antiviral drugs are available. Recent outbreaks in EU countries and China have highlighted the critical role of antiviral research in combating this disease. We have previously shown that apigenin, a naturally occurring plant flavone, possesses significant anti-ASFV activity. However, apigenin is practically insoluble in highly polar solvents and it occurs typically in derivative forms in plants. Here we screened several commercially available apigenin derivatives for their ability to inhibit ASFV Ba71V strain in Vero cells. Among them, genkwanin showed significant inhibition of ASFV, reducing viral titer from 6.5 ± 0.1 to 4.75 ± 0.25 log TCID/ml in a dose-dependent manner (IC 50 = 2.9 μM and SI = 205.2). Genkwanin reduced the levels of ASFV early and late proteins, as well as viral DNA synthesis. Our further experiments indicated that genkwanin is able to inhibit ASFV infection at entry and egress stages. Finally, genkwanin displayed potent antiviral activity against highly virulent ASFV isolate currently circulating in Europe and China, emphasizing its value as candidate for antiviral drug development. • Several apigenin derivatives were screened to identify potential inhibitor of ASFV in a dose dependent manner. • Genkwanin inhibits ASFV infection in Vero cells and porcine macrophages. • Genkwanin demonstrates a potent effect on virus entry and egress stages. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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12. Genistein inhibits African swine fever virus replication in vitro by disrupting viral DNA synthesis.
- Author
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Arabyan, Erik, Hakobyan, Astghik, Kotsinyan, Armen, Karalyan, Zaven, Arakelov, Vahram, Arakelov, Grigor, Nazaryan, Karen, Simonyan, Anna, Aroutiounian, Rouben, Ferreira, Fernando, and Zakaryan, Hovakim
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GENISTEIN , *AFRICAN swine fever , *VIRAL replication , *DNA synthesis , *DRUG development , *THERAPEUTICS - Abstract
African swine fever virus (ASFV) is the causal agent of a highly-contagious and fatal disease of domestic pigs, leading to serious socio-economic consequences in affected countries. Once, neither an anti-viral drug nor an effective vaccines are available, studies on new anti-ASFV molecules are urgently need. Recently, it has been shown that ASFV type II topoisomerase (ASFV-topo II) is inhibited by several fluoroquinolones (bacterial DNA topoisomerase inhibitors), raising the idea that this viral enzyme can be a potential target for drug development against ASFV. Here, we report that genistein hampers ASFV infection at non-cytotoxic concentrations in Vero cells and porcine macrophages. Interestingly, the antiviral activity of this isoflavone, previously described as a topo II poison in eukaryotes, is maximal when it is added to cells at middle-phase of infection (8 hpi), disrupting viral DNA replication, blocking the transcription of late viral genes as well as the synthesis of late viral proteins, reducing viral progeny. Further, the single cell electrophoresis analysis revealed the presence of fragmented ASFV genomes in cells exposed to genistein, suggesting that this molecule also acts as an ASFV-topo II poison and not as a reversible inhibitor. No antiviral effects were detected when genistein was added before or at entry phase of ASFV infection. Molecular docking studies demonstrated that genistein may interact with four residues of the ATP-binding site of ASFV-topo II (Asn-144, Val-146, Gly-147 and Leu-148), showing more binding affinity (−4.62 kcal/mol) than ATP 4− (−3.02 kcal/mol), emphasizing the idea that this viral enzyme has an essential role during viral genome replication and can be a good target for drug development against ASFV. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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13. Energy-dependent protein folding: modeling how a protein folding machine may work.
- Author
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Sahakyan H, Nazaryan K, Mushegian A, and Sorokina I
- Subjects
- Peptides, Protein Conformation, Proteins, Artificial Intelligence, Protein Folding
- Abstract
Background: Proteins fold robustly and reproducibly in vivo , but many cannot fold in vitro in isolation from cellular components. Despite the remarkable progress that has been achieved by the artificial intelligence approaches in predicting the protein native conformations, the pathways that lead to such conformations, either in vitro or in vivo , remain largely unknown. The slow progress in recapitulating protein folding pathways in silico may be an indication of the fundamental deficiencies in our understanding of folding as it occurs in nature. Here we consider the possibility that protein folding in living cells may not be driven solely by the decrease in Gibbs free energy and propose that protein folding in vivo should be modeled as an active energy-dependent process. The mechanism of action of such a protein folding machine might include direct manipulation of the peptide backbone. Methods: To show the feasibility of a protein folding machine, we conducted molecular dynamics simulations that were augmented by the application of mechanical force to rotate the C-terminal amino acid while simultaneously limiting the N-terminal amino acid movements. Results: Remarkably, the addition of this simple manipulation of peptide backbones to the standard molecular dynamics simulation indeed facilitated the formation of native structures in five diverse alpha-helical peptides. Steric clashes that arise in the peptides due to the forced directional rotation resulted in the behavior of the peptide backbone no longer resembling a freely jointed chain. Conclusions: These simulations show the feasibility of a protein folding machine operating under the conditions when the movements of the polypeptide backbone are restricted by applying external forces and constraints. Further investigation is needed to see whether such an effect may play a role during co-translational protein folding in vivo and how it can be utilized to facilitate folding of proteins in artificial environments., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Sahakyan H et al.)
- Published
- 2021
- Full Text
- View/download PDF
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