Abstract
Dengue virus (DENV) and Zika virus (ZIKV) are flaviviruses transmitted by Aedes spp. mosquitoes, causing a spectrum of symptoms ranging from mild fevers and joint pain to severe damage to vital organs, including the kidneys, brain, and liver. Unfortunately, there are currently no specific treatments for these viruses. The NS2B/NS3 serine protease has been recognized as a crucial therapeutic target due to its pivotal role in viral replication. Herein, several molecular modeling techniques were employed to search for novel allosteric inhibitors against DENV and ZIKV NS2B/NS3 proteases from a set of 545 in-house compounds. Virtual screening based on molecular docking and MM/GBSA-based free energy calculations indicated that, among 545 derivatives, four compounds demonstrated high binding affinity against both targets, including two sulfonamide-vinyl sulfone hybrids (cpd48_e and cpd50_e), one sulfonamide-chalcone analog (cpd48), and one berberine-cinnamic acid derivative (DN071_f). Their molecular complexation was driven mainly by van der Waals forces rather than electrostatic attraction. Several residues at the enzyme allosteric site, particularly K74, L149, and N152 (DENV) and L76, I123, N152, and V155 (ZIKV), were identified as binding hotspots for the screened compounds. Drug-likeness predictions based on Lipinski's rule of five further supported their potential as drug candidates. Overall, these findings provide valuable insights for the future design and development of novel antiviral drugs targeting the DENV and ZIKV NS2B/NS3 proteases.