Computational Insights Into the Inhibition of Novel Imidazole [1,2‐α] Pyrimidine Derivatives Against Influenza A Virus

Abstract Hemagglutinin (HA) is an important glycoprotein on the surface of influenza virus, which is involved in virus attachment to host cells through viral membrane and fusion with host cell membrane to form host cells. H3N2 inhibitors can bind to hydrophobic cavities at the HA pre‐polymer interface, preventing its conformational rearrangement and ultimately inhibiting membrane fusion. In this study, 46 imidazole [1, 2‐α] pyrimidine derivatives were analyzed using two different analytical methods (CoMFA and CoMSIA) and a reliable 3D‐QSAR model was established. On this basis, 10 new compounds with good predictive activity were designed. The pharmacodynamics of three new compounds A1, A5 and A9 were evaluated by molecular docking and ADME/T. Based on molecular dynamics simulations, free binding energy is calculated and other important evaluation criteria are analyzed. The results showed that the ring conformation formed by the essential amino acids VAL55, ILE56, GLU57, LYS58 and YHR59 on the F chain remained basically unchanged with the extension of simulation time, and tended to converge to the compound. Further structural optimization of the candidate active compound A1 will provide the necessary theoretical basis for developing and evaluating the efficacy of novel H3N2 inhibitors.