Abstract
The NS2B-NS3 protease and the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are interlinked with viral genome replication. Therefore, inhibiting their activities would reduce the viral loads in patients. To identify molecules that can strongly bind to the substrate binding site of the NS2B-NS3 protease of the ZIKV, interactions of several aryl benzoyl hydrazide (ABH) derivatives (10b, 10c, 10g, 11p, and 11q) and some anti-influenza drugs (Zanamivir, Laninamivir, Baloxavir, Oseltamivir, Rimantadine, Peramivir, and Amantadine) with the ZIKV NS2B-NS3 protease are studied herein by using combined density functional theoretic, docking, molecular dynamics (100 ns MD simulations), and free-energy methods. Among these molecules, 11q binds strongly to the ZIKV protease with a ΔG(bind) of about - 15.70 ± 2.30 kcal/mol. Its binding to the NS2B-NS3 protease is stronger than the anti-influenza drugs studied herein. Notably, the binding affinity of 11q is found to be approximately 4 kcal/mol more negative than that of SYC-1307, a known allosteric inhibitor of the ZIKV protease. 11q is also found to bind to the NTP and allosteric sites of the ZIKV RdRp. However, the binding of 11q to the NTP site of RdRp is preferred over that of the allosteric site. Interestingly, extending the simulation time to 500 ns did not alter the structure of 11q bound to both ZIKV protease and the NTP site of RdRp. However, 11q showed a higher affinity toward the NS2B-NS3 protease than the NTP site of RdRp. Computed ADMET parameters, Lipinski's rule of five, and binding affinities suggest that 11q would be a better drug candidate against ZIKV infections. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00395-5.