title: Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2.
abstract: 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 IC(50)s 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.
authors: Department of Chemistry, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6059, United States.
authors: Jun
authors: J
authors: Wang
authors: Chunlong
authors: C
authors: Ma
authors: Giacomo
authors: G
authors: Fiorin
authors: Vincenzo
authors: V
authors: Carnevale
authors: Tuo
authors: T
authors: Wang
authors: Fanghao
authors: F
authors: Hu
authors: Robert A
authors: RA
authors: Lamb
authors: Lawrence H
authors: LH
authors: Pinto
authors: Mei
authors: M
authors: Hong
authors: Michael L
authors: ML
authors: Klein
authors: William F
authors: WF
authors: DeGrado
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D024882:Drug Resistance, Viral; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics; D007251:Influenza, Human / Q000188:drug therapy*; D056004:Molecular Dynamics Simulation; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D010948:Viral Plaque Assay; D000086082:Viroporin Proteins
chemical_list: D000998:Antiviral Agents; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins