Structure-based virtual screening and fragment replacement to design novel inhibitors of Coxsackievirus A16 (CVA16)

Numerous studies have shown that hand, foot and mouth disease (HFMD) pathogen Coxsackievirus A16 (CVA16) can also cause severe neurological complications and even death. Currently, there is no effective drugs and vaccines for CVA16. Therefore, developing a drug against CVA16 has become critical. In this study, we conducted two strategies-virtual screening (VS) and fragment replacement to obtain better candidates than the known drug GPP3. Through VS, 37 candidate drugs were screened (exhibiting a lower binding energy than GPP3). After toxicity evaluations, we obtained five candidates, analysed their binding modes and found that four candidates could enter the binding pocket of the GPP3. In another strategy, we analysed the four positions in GPP3 structures by the FragRep webserver and obtained a large number of candidates after replacing different functional groups, we obtained eight candidates (that target the four positions above) with the combined binding score and synthetic accessibility evaluations. AMDock software was uniformly utilized to perform molecular docking evaluation of the candidates with binding activity superior to that of GPP3. Finally, the selected top three molecules (Lapatinib, B001 and C001) and its interaction with CAV16 were validated by molecular dynamics (MD) simulation. The results indicated that all three molecules retain inside the pocket of CAV16 receptor throughout the simulation process, and he binding energy calculated from the MD simulation trajectories also support the strong affinity of the top three molecules towards the CVA16. These results will provide new ideas and technical guidance for designing and applying CVA16 therapeutics.