3D-QSAR and molecular docking studies of peptide-hybrids as dengue virus NS2B/NS3 protease inhibitors

Global warming and climate change have made dengue disease a global health issue. More than 50 % of the world's population is at danger of dengue virus (DENV) infection, according to the World Health Organization (WHO). Therefore, a clinically approved dengue fever vaccination and effective treatment are needed. Peptide medication development is new pharmaceutical research. Here we intend to recognize the structural features inhibiting the DENV NS2B/NS3 serine protease for a series of peptide-hybrid inhibitors (R₁-R₂-Lys-R₃-NH₂) by the 3D-QSAR technique. Comparative molecular field analysis (q² = 0.613, r² = 0.938, r²_pred = 0.820) and comparative molecular similarity indices analysis (q² = 0.640, r² = 0.928, r²_pred = 0.693) were established, revealing minor, electropositive, H-bond acceptor groups at the R₁ position, minor, electropositive, H-bond donor groups at the R₂ position, and bulky, hydrophobic groups at the R₃ position for higher inhibitory activity. Docking studies revealed extensive H-bond and hydrophobic interactions in the binding of tripeptide analogues to the NS2B/NS3 protease. This study provides an insight into the key structural features for the design of peptide-based inhibitors of DENV NS2B/NS3 protease.