Use of a pharmacophore model to discover a new class of influenza endonuclease inhibitors.
Data from both our own and literature studies of the biochemistry and inhibition of influenza virus endonuclease was combined with data on the mechanism of action and the likely active site mechanism to propose a pharmacophore. The pharmacophore was used to design a novel structural class of inhibitors, some of which were found to have activities similar to that of known influenza endonuclease inhibitors and were also antiviral in cell culture.
Parkes
Kevin E B
KE
Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Herts, AL7 3AY, UK. kevin.parkes@medivir.com
Ermert
Philipp
P
Fässler
Jürg
J
Ives
Jane
J
Martin
Joseph A
JA
Merrett
John H
JH
Obrecht
Daniel
D
Williams
Glyn
G
Klumpp
Klaus
K
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry; D016208:Databases, Factual; D004285:Dogs; D004720:Endonucleases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology; D009981:Influenza B virus / Q000187:drug effects / Q000201:enzymology; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D002087:Butyrates; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D007651:Keto Acids; D010797:Phthalimides; D012321:DNA-Directed RNA Polymerases; D004720:Endonucleases