QSAR study of N-substituted Oseltamivir derivatives as potent avian influenza virus H5N1 inhibitors using quantum chemical descriptors and statistical methods

Abstract: Insilico modelling studies were executed on thirty two N-substituted Oseltamivir derivatives as inhibitors of influenza virus H5N1. Robust validated quantitative structure-activity relationship (QSAR) approaches have been investigated to explore the important structural requirements essential to design potent anti-influenza virus H5N1 inhibitors. The density functional theory (DFT) calculation with Becke’s three-parameter hybrid method and the Lee-Yang-Parr B3LYP functional employing 6–31G (d) basis set is used to calculate quantum chemical descriptors. The dataset was randomly divided into training and test sets comprising 25 and 7 compounds, respectively. Twenty models were established by changing the compounds of the sets and further were applied to calculate the predict pIC50 values of the 7 compounds in the test set. All constructed models were individually validated internally as well as externally along with Y-Randomization according to the OECD principles for QSAR model validation and the Golbraikh and Tropsha’s criteria of models acceptance. Model 5 is selected with higher R², R²test and Q²cv values (R² = 0.902, R²adj = 0.888, MSE = 0.094, R²test= 0.872, Q²cv = 0.857). It is very interesting to find that the anti-influenza H5N1 of these compounds appear to be mainly governed by three molecular descriptors, i.e. lowest unoccupied molecular orbital energy (ELUMO), energy of the molecular orbital below HOMO (EHOMO-1) and number of atoms (NA). Here the possible mechanism of action of these compounds was analysed and discussed, in particular, important structural requirements for enhanced H5N1 virus inhibitor activity could be reached by reducingthe molecular size and introducing stronger electron accepting ability groups with small atoms and more protons to the N-substituted Oseltamivir derivatives. Based on the best proposed QSAR model, some new compounds with higher neuraminidase inhibitor have been theoretically designed. Such results can offer useful theoretical references for future experimental works.