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Molecular Docking and QSAR Studies on Substituted Acyl(thio)urea and Thiadiazolo [2,3‐α] Pyrimidine Derivatives as Potent Inhibitors of Influenza Virus Neuraminidase
Author(s) -
Sun Jiaying,
Cai Shaoxi,
Mei Hu,
Li Jian,
Yan Ning,
Wang Qin,
Lin Zhihua,
Huo Danqun
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2010.01006.x
Subject(s) - quantitative structure–activity relationship , chemistry , molecular dynamics , hydantoin , molecular model , docking (animal) , thiourea , chemical similarity , molecular descriptor , similarity (geometry) , neuraminidase , computational chemistry , stereochemistry , structural similarity , organic chemistry , biochemistry , enzyme , medicine , nursing , artificial intelligence , computer science , image (mathematics)
Surflex–Dock was employed to dock 36 thiourea and thiadiazolo [2,3‐α] 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 pIC 50 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 ( r 2 ) 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 ( q 2 ) 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 ( r 2 test ) 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.