- Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2
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Influenza A virus M2 (A/M2) forms a homotetrameric proton selective channel in the viral membrane. It has been the drug target of antiviral drugs such as amantadine and rimantadine. However, most of the current virulent influenza A viruses carry drug-resistant mutations alongside the drug binding site, such as S31N, V27A, and L26F, etc., each of which might be dominant in a given flu season. Among these mutations, the V27A mutation was prevalent among transmissible viruses under drug selection pressure. Until now, V27A has not been successfully targeted by small molecule inhibitors, despite years of extensive medicinal chemistry research efforts and high throughput screening. Guided by molecular dynamics (MD) simulation of drug binding and the influence of drug binding on the dynamics of A/M2 from earlier experimental studies, we designed a series of potent spirane amine inhibitors targeting not only WT, but also both A/M2-27A and L26F mutants with IC50s similar to that seen for amantadine's inhibition of the WT channel. The potencies of these inhibitors were further demonstrated in experimental binding and plaque reduction assays. These results demonstrate the power of MD simulations to probe the mechanism of drug binding as well as the ability to guide design of inhibitors of targets that had previously appeared to be undruggable.
- Wang, Jun,Ma, Chunlong,Fiorin, Giacomo,Carnevale, Vincenzo,Wang, Tuo,Hu, Fanghao,Lamb, Robert A.,Pinto, Lawrence H.,Hong, Mei,Klein, Michael L.,Degrado, William F.
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Read Online
- CARBOXAMIDE DERIVATIVES
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
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Paragraph 0451-0452
(2015/12/17)
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- Free-radical carbo-oximation of olefins and subsequent radical-ionic cascades
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A sequential carbo-formylation cascade has been developed, involving a free-radical carbo-oximation process, followed by the hydrolysis of the oxime ether. For this purpose, we designed a new SEM O-protected sulfonyl oxime, which enable both rapid radical addition and hydrolysis under mild conditions. The resulting aldehyde-esters were then engaged in various nucleophilic cascades, such as Sakurai allylations or domino-Mukaiyama aldol condensation/ lactonizations. Addition of an amine and TMSCN similarly led after Strecker reaction/lactamization to α-cyano-piperidinones in good overall yield. Finally, a Pictet-Spengler/lactamization sequence was devised, which open a new entry toward the tricyclic core of eburnan alkaloids.
- Landais, Yannick,Robert, Frédéric,Godineau, Edouard,Huet, Laurent,Likhite, Nachiket
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supporting information
p. 10073 - 10080
(2013/11/06)
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- Inhibitors Of The Influenza A Virus M2 Proton Channel
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Provided are compounds that are capable of modulating the activity of the influenza A virus via interaction with the M2 transmembrane protein. Also provided are methods for treating an influenza A-affected disease state or infection comprising administering a composition comprising one or more compounds that have been identified as being capable of interaction with the M2 protein.
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Page/Page column 8-9
(2012/02/06)
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- ACID-LABILE ESTER MONOMER HAVING SPIROCYCLIC STRUCTURE, POLYMER, RESIST COMPOSITION, AND PATTERNING PROCESS
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An acid-labile ester monomer of spirocyclic structure has formula (1) wherein Z is a monovalent group having a polymerizable double bond, X is a divalent group which forms a cyclopentane, cyclohexane or norbornane ring, R2 is H or monovalent hydrocarbon, R3 and R4 are H or monovalent hydrocarbon, or R3 and R4, taken together, stand for a divalent group which forms a cyclopentane or cyclohexane ring, and n is 1 or 2. A polymer obtained from the acid-labile ester monomer has so high reactivity in acid-catalyzed elimination reaction that the polymer may be used to formulate a resist composition having high resolution.
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- HYDROGENATED BENZO (C) THIOPHENE DERIVATIVES AS IMMUNOMODULATORS
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The invention relates to novel thiophene derivatives, their preparation and their use as pharmaceutically active compounds. Said compounds particularly act as immunosuppressive agents.
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Page/Page column 73
(2010/11/24)
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