Structure-based high-throughput screening and identification of novel inhibitors of HEV helicase

Hepatitis E virus (HEV) causes acute liver inflammation in general population as well as chronic liver diseases in immunocompromised patients. Currently, there no universally assessible vaccine or approved drugs for chronic hepatitis E. We used the 3D model of HEV helicase for high-throughput virtual screening of 20 million ligands (MCULE database). The physicochemical, pharmacokinetic, drug-likeness and medicinal-chemistry properties of the top hit molecules were analyzed, following molecular docking and molecular dynamics (MD) simulation at 100 ns. Of the top 50 hits, thirteen best molecules (≤‒8.0 kcal/mol) complied with the predicted physicochemical, pharmacokinetic, drug-likeness and medicinal-chemistry properties. Finally, two molecules MCULE-3036744764-0-1 and MCULE-6712551813-0-39 were selected as the most suitable helicase-inhibitor candidates. Further, molecular docking and MD simulation results of helicase and its two complexes clearly indicated their structural stability and compactness. The Prime/MM-GBSA calculated free-energy of helicase and its MCULE-3036744764-0-1 and MCULE-6712551813-0-39 complexes were ‒31.57, ‒34.90 and ­‒37.17 kcal/mol, respectively. In conclusion, our data therefore, warrants their further experimental validations towards developing future anti-HEV drugs.