Design of Broad-Spectrum Inhibitors of Influenza A Virus M2 Proton Channels: A Molecular Modeling Approach

Klimochkin, Yu. N.; Shiryaev, Vadim A.; Петров, Павел Валерьевич; Radchenko, Eugene V.; Palyulin, V. A.; Зефиров, Н. С.

doi:10.2174/1573409912666160505113408

Cited by 7 publications

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“…Molecular dynamics simulations, conducted using the procedure described in [ 21 ], indicate ( Figure 2 ), that compound 3 is located in the transmembrane domain of the M2 proton channel of the S31N mutant influenza virus, in the region of amino acids 45–49 of different chains of the M2 tetramer, and does not have direct interactions with the pharmacologically relevant binding site of Rimantadine in the region of amino acid 31 [ 22 ]. This may explain high activity of compound 3 against the Rimantadine-resistant strain of the virus; however additional studies are needed, to establish the mechanism of the antiviral action of 3 .…”

Section: Resultsmentioning

confidence: 99%

“…For molecular dynamics simulations, the apo-M2 conductance domain structure (residues 23–60) (the lowest-energy conformer) was obtained from the Protein Data Bank for the S31N mutant influenza virus (PDB: 2KIH). The starting structure of the M2CD complex with compound 3 was obtained by means of molecular docking to the region of amino acids 25–50 (the ligand structure and M2 channel model were prepared as described in [ 21 ]) using the AutoDock Vina 1.1.2 software [ 26 ] (grid box 11.25 Å × 11.25 Å × 11.25 Å, grid center size x = −23.987 Å, y = 4.634 Å, z = −6.149 Å, exhaustiveness = 20), complexes with the best value of scoring function was selected).…”

Section: Methodsmentioning

confidence: 99%

“…Molecular dynamics simulations were performed as described in [ 21 ] using the CHARMM-GUI Web service [ 27 , 28 , 29 , 30 ]. For the analysis and visualization of the results, the cpptraj software [ 31 ] in the AmberTools 18 package [ 32 ] and UCSF Chimera software [ 26 ] were used.…”

Section: Methodsmentioning

confidence: 99%

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Bicyclic Isoxazoline Derivatives: Synthesis and Evaluation of Biological Activity

et al. 2022

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The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective target–ligand interactions or are less prone to the development of resistance. Among the works of the last decade, a literature search revealed spirothiazamenthane, which has served as a lead in the development of derivatives active against resistant viral strains. In this work, we studied the novel molecular scaffold, which resembles spirothiazamenthane, but combines isoxazoline as a heterocycle and cyclooctane ring as a hydrophobic part of the structure. The synthesis of new 3-nitro- and 3-aminoisoxazolines containing spiro-fused or 1,2-annelated cyclooctane fragments was achieved by employing 1,3-dipolar cycloaddition of 3-nitro-4,5-dihydroisoxazol-4-ol 2-oxide or tetranitromethane-derived alkyl nitronates with non-activated alkenes. A series of spiro-sulfonamides was obtained by the reaction of 3-aminoisoxazoline containing a spiro-fused cyclooctane residue with sulfonyl chlorides. Preliminary screening of the compounds for antiviral, antibacterial, antifungal and antiproliferative properties in vitro revealed 1-oxa-2-azaspiro[4.7]dodec-2-en-3-amine and 3a,4,5,6,7,8,9,9a-octahydrocycloocta[d]isoxazol-3-amine with activity against the influenza A/Puerto Rico/8/34 (H1N1) virus in the submicromolar range, and high values of selectivity index. Further study of the mechanism of the antiviral action of these compounds, and the synthesis of their analogues, is likely to identify new agents against resistant viral strains.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Bicyclic Isoxazoline Derivatives: Synthesis and Evaluation of Biological Activity

et al. 2022

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“…To supplement these shortcomings of influenza vaccines, numerous antiviral compounds have been developed to target and inhibit crucial components of the infectious pathway of the virus. − The influenza A M2 proton channel is one of those targets, and the high mutation rate of the influenza virus has led to almost complete resistance against all known M2 inhibitors within four decades of their use. , M2 plays a crucial role in the infection of the host cell during the viral infectivity cycle . Therefore, effective approaches for studying both potential M2 inhibitors and the development of resistance toward inhibitors are obviously of great importance. − …”

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confidence: 99%

A Robust Proton Flux (pHlux) Assay for Studying the Function and Inhibition of the Influenza A M2 Proton Channel

et al. 2018

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The M2 protein is an important target for drugs in the fight against the influenza virus. Because of the emergence of resistance against antivirals directed toward the M2 proton channel, the search for new drugs against resistant M2 variants is of high importance. Robust and sensitive assays for testing potential drug compounds on different M2 variants are valuable tools in this search for new inhibitors. In this work, we describe a fluorescence sensor-based assay, which we termed "pHlux", that measures proton conduction through M2 when synthesized from an expression vector in Escherichia coli. The assay was compared to a previously established bacterial potassium ion transport complementation assay, and the results were compared to simulations obtained from analysis of a computational model of M2 and its interaction with inhibitor molecules. The inhibition of M2 was measured for five different inhibitors, including Rimantadine, Amantadine, and spiro type compounds, and the drug resistance of the M2 mutant variants (swine flu, V27A, and S31N) was confirmed. We demonstrate that the pHlux assay is robust and highly sensitive and shows potential for high-throughput screening.

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Molecular design, synthesis and biological evaluation of cage compound-based inhibitors of hepatitis C virus p7 ion channels

Shiryaev

Radchenko

Palyulin

et al. 2018

European Journal of Medicinal Chemistry

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Design of Broad-Spectrum Inhibitors of Influenza A Virus M2 Proton Channels: A Molecular Modeling Approach

Cited by 7 publications

References 0 publications

Bicyclic Isoxazoline Derivatives: Synthesis and Evaluation of Biological Activity

Bicyclic Isoxazoline Derivatives: Synthesis and Evaluation of Biological Activity

A Robust Proton Flux (pHlux) Assay for Studying the Function and Inhibition of the Influenza A M2 Proton Channel

Molecular design, synthesis and biological evaluation of cage compound-based inhibitors of hepatitis C virus p7 ion channels

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