QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR

Abstract

The recent wide spreading of the H5N1 avian influenza virus (AIV) in Asia, Europe and Africa and its ability to cause fatal infections in human has raised serious concerns about a pending global flu pandemic. Neuraminidase (NA) inhibitors are currently the only option for treatment or prophylaxis in humans infected with this strain. However, drugs currently on the market often meet with rapidly emerging resistant mutants and only have limited application as inadequate supply of synthetic material. To dig out helpful information for designing potent inhibitors with novel structures against the NA, we used automated docking, CoMFA, CoMSIA, and HQSAR methods to investigate the quantitative structure-activity relationship for 126 NA inhibitors (NIs) with great structural diversities and wide range of bioactivities against influenza A virus. Based on the binding conformations discovered via molecular docking into the crystal structure of NA, CoMFA and CoMSIA models were successfully built with the cross-validated q (2) of 0.813 and 0.771, respectively. HQSAR was also carried out as a complementary study in that HQSAR technique does not require 3D information of these compounds and could provide a detailed molecular fragment contribution to the inhibitory activity. These models also show clearly how steric, electrostatic, hydrophobicity, and individual fragments affect the potency of NA inhibitors. In addition, CoMFA and CoMSIA field distributions are found to be in well agreement with the structural characteristics of the corresponding binding sites. Therefore, the final 3D-QSAR models and the information of the inhibitor-enzyme interaction should be useful in developing novel potent NA inhibitors.

The conformational analysis and proton transfer of neuraminidase inhibitors: a theoretical study

“…[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Scheme 1 lists several potent NA inhibitors, including zanamivir, oseltamivir carboxylate and BA. Note that oseltamivir is the prodrug of oseltamivir carboxylate (GS4071, compound 2).…”

Genetic characterization of H5N1 influenza viruses isolated from chickens in Indonesia in 2010

“…Analysis of the NA amino acids showed that these eight isolates have the 20-amino acid stalk deletion that is associated with adaptation of influenza viruses from aquatic birds to territory poultry [7–10]. These eight isolates do not possess any of the amino acids in the catalytic and framework sites that are responsible for resistance to NA-inhibitor drugs [11–14]. Group A viruses did have a unique potential glycosylation site at amino acid position 50, which has also been observed in some H5N1 viruses isolated in China during 2001–2003, according to the sequence data in the influenza databases.…”

Fragment‐based quantitative structure–activity relationship (FB‐QSAR) for fragment‐based drug design

“…The molecular structures of 48 NA inhibitors used in this study are listed in Table 1, which are collected from literatures. [41][42][43] Ten physicochemical properties are used in the FB-QSAR study. The codes and the physical implications of the 10 properties are listed in Table 2, including the charge descriptors, molecular shape descriptors, interaction descriptors, and solvation descriptors.…”