Molecular docking and QSAR studies on substituted acyl(thio)urea and thiadiazolo [2,3-alpha] pyrimidine derivatives as potent inhibitors of influenza virus neuraminidase.
Surflex-Dock was employed to dock 36 thiourea and thiadiazolo [2,3-alpha] pyrimidine derivatives into neuraminidase 1a4g. Molecular docking results showed that hydrogen bonding, electrostatic, and hydrophobic features were important factors affecting inhibitory activities of these neuraminidase inhibitors. Moreover, there was a significant correlation between the predicted binding affinity (total scores) and experimental pIC50 values with correlation coefficient r=0.846 and p<0.0001. Hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis were used to develop quantitative structure-activity relationship models. Squared multiple correlation coefficients (r2) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.899, 0.878, and 0.865, respectively. Squared cross-validated correlation coefficient (q2) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models was in turn 0.628, 0.656, and 0.509. In addition, squared multiple correlation coefficients for test set (r2test) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.558, 0.667, and 0.566, respectively. The most active sample ID 2 was taken as a template molecule to design new molecules. Based on the comparative molecular field analysis model, new compounds were designed by LeapFrog. Seven new compounds with improved binding energy and predicted activities were finally obtained.
Sun
Jiaying
J
College of Bioengineering, Chongqing University, Chongqing 400044, China. wy7472@126.com
Cai
Shaoxi
S
Mei
Hu
H
Li
Jian
J
Yan
Ning
N
Wang
Qin
Q
Lin
Zhihua
Z
Huo
Danqun
D
D000998:Antiviral Agents / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D009975:Orthomyxoviridae / Q000201:enzymology* / Q000378:metabolism; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D009439:Neuraminidase; D013890:Thiourea