Use of a Pharmacophore Model To Discover a New Class of Influenza Endonuclease Inhibitors

Abstract

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.

Mutational Analysis of the Binding Pockets of the Diketo Acid Inhibitor L-742,001 in the Influenza Virus PA Endonuclease

“…These discoveries were soon followed by others, resulting in a chemical variety of reported influenza virus endonuclease inhibitors, e.g., N-hydroxamic acid and N-hydroxyimide compounds (23), tetramic acid series and diketobutanoates (24), polyphenolic catechins (25), phenethylphenylphthalimide analogs derived from thalidomide (26), macrocyclic bisbibenzyls (27), a group of compounds bearing distinct pharmacophoric fragments (28), and 3-hydroxyquinolin-2(1H)-ones (29). An effort was also made to define the essential pharmacophore from the available structure-activity relationship (24). However, truly rational and structure-based drug design became possible only after the influenza virus PA protein was identified as the endonuclease subunit and the crystal structure of PA-Nter was available (14,15).…”

“…Another endonuclease inhibitor identified by these investigators is flutimide, a fully substituted 1-hydroxy-3H-pyrazine-2,6-dione isolated from a fungus (21), which served as a lead compound for developing a series of more potent aromatic analogues (22). These discoveries were soon followed by others, resulting in a chemical variety of reported influenza virus endonuclease inhibitors, e.g., N-hydroxamic acid and N-hydroxyimide compounds (23), tetramic acid series and diketobutanoates (24), polyphenolic catechins (25), phenethylphenylphthalimide analogs derived from thalidomide (26), macrocyclic bisbibenzyls (27), a group of compounds bearing distinct pharmacophoric fragments (28), and 3-hydroxyquinolin-2(1H)-ones (29). An effort was also made to define the essential pharmacophore from the available structure-activity relationship (24).…”

2-Hydroxyisoquinoline-1,3(2H,4H)-dione

“…For the biological properties of the title compound, see: Parkes et al (2003); Hang et al (2004); Billamboz et al (2008). For a related structure, see: Miao et al (1995).…”

“…The title compound is known to inhibit metalloenzymes such as influenza endonuclease (Parkes et al, 2003), HIV-1 reverse transcriptase RNase H (Hang et al, 2004), and HIV-1 integrase (Billamboz et al, 2008). Here we report the crystal structure of the title compound, which was obtained from the deprotection of 2-benzyloxyisoquinoline-1,3(2H,4H)-dione by the use of boron tribromide.…”

Virtual Screening and Biological Validation of Novel Influenza Virus PA Endonuclease Inhibitors

“…Besides, the spatial disposition of these metal ligator (ML) moieties is critical to achieve effective inhibition of the influenza virus PA endonuclease. In particular, the oxygens should be displaced at the vertices of a triangle with dimensions of 2.60− 2.80, 2.60−2.80, and 4.50−5.50 Å for the model proposed by Parkes, 32 and of 2.56−2.87, 2.22−2.62, and 3.49−4.51 Å for that put forward by Kim. 33 Our best three pharmacophore models shown in Figure 2 (PH4-2, PH4-3, and PH4-9) were in nice agreement with these requirements (i.e., ML1-ML2-ML3 interfeature distances are 2.75, 2.96, and 4.46 Å).…”