“A comprehensive in-silico analysis reveals acylsulfonamide-based FDA approved drugs to be potential pan flavivirus antivirals targeting NS3 protease”

The Orthoflavivirus genus has 70 arthropod-borne viruses causing epidemics globally. The mosquito-borne flavivirus cluster harbors fatal Human pathogens. Several vaccine candidates, like Dengvaxia and YF-17D, are available to target specific flaviviruses albeit with significant constraints. Despite decades of research, no effective FDA-approved pan flavivirus vaccine or broad-spectrum small molecule antivirals are available to target these viruses. Small-molecule drug discovery efforts have achieved limited success, often targeting a single strain. Many of these viruses have serological differences and genotypic variation within the serotypes. The structural architecture of the mosquito-borne flaviviruses is similar both at the genomic and proteomic levels. This allows for developing drugs or vaccines with broad spectrum potency. In this study, using sequence and structure-based alignment, we found conserved and druggable allosteric sites in the NS2B-NS3 protease of nine flaviviruses. Using a library of 70 FDA-approved small molecule anti-viral drugs, we found five, Paritaprevir, Simpeprevir, Glecaprevir, Grazoprevir, and Voxilaprevir, all derivatives of acylsulfonamide scaffold, approved against HCV NS3/4A protease, to have comparable binding affinities, ranging from -12 to -9 Kcal/mol, across all the nine flaviviruses. The protein-drug interaction profiles have revealed the same atoms of the drugs involved in interactions in both HCV and the flaviviruses, albeit at the allosteric site in the latter’s case. In-depth MD simulation analysis has revealed simeprevir and paritaprevir as the most potential candidates with ‘broad-spectrum’, acting against species from multiple groups of MBFV cluster, flaviviral activity, targeting the flaviviral NS3 protease.