| Neuraminidase (also called sialidase) is a glycoprotein attached to the film of influenza virus, it plays an important role in the viral life cycle. The novel cyclohexene inhibitors block the transmission and pervasion of resistant strains. First of all, this paper explored 65 oseltamivir derivatives using three dimensional quantitative structure activity relationship(3D-QSAR) reported by the recent literature. The best result indicates that the cross validation coefficient (q2), correlation coefficient (r2) of comparative molecular field analysis (CoMFA)and comparative molecular similarity analysis (CoMSIA) are q2=0.819, r2=0.992; q2=0.863,r2=0.992; respectively. According to analysis on contour maps of five force filed, the introduction of hydrophobic substituents on the location of the C5-NH2 (such as biphenyl ring class) is beneficial to improve oseltamivir analogs activity. In addition, we could study the interaction of small molecules binding with neuraminidase active sites, and the key amino acid residues included Arg371, Arg292, Arg 152 and Arg118, etc. Furthermore, the molecular dynamics quantify the binding affinity between receptor and ligands. ADMET-linked descriptors were predicting the pharmacokinetic properties for the selection of the data set molecules and offering valuable information for the design and synthesis of novel antiviral drugs. Target molecule 2501 passed the entire ADMET test.In order to verify the reliability of the calculation results, some new inhibitors were synthesized. And the representative compounds were tested by biological evaluation. It shows that the inhibitory effect of compound 2501 against neuraminidase is strong, exhibiting the similar inhibition with oseltamivir. The experimental results are in good agreement with the theoretical calculation, that is to say, the biphenyl group can effectively enhance the inhibition ability. The study in this paper provided guidance for the new drug design. |
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