Aminopyrimidine Derivatives as Multiflavivirus Antiviral Compounds Identified from a Consensus Virtual Screening Approach
Mateus Sá Magalhães Serafim, Thales Kronenberger, Rafael E. O. Rocha, Amanda Del Rio Abreu Rosa, Thaysa Lara Gonçalves Mello, Antti Poso, Rafaela Salgado Ferreira, Jônatas Santos Abrahão, Erna Geessien Kroon, Bruno Eduardo Fernandes Mota, Vinícius Gonçalves Maltarollo
Abstract
Around three billion people are at risk of infection by the dengue virus (DENV) and potentially other flaviviruses. Worldwide outbreaks of DENV, Zika virus (ZIKV), and yellow fever virus (YFV), the lack of antiviral drugs, and limitations on vaccine usage emphasize the need for novel antiviral research. Here, we propose a consensus virtual screening approach to discover potential protease inhibitors (NS3 pro ) against different flavivirus. We employed an in silico combination of a hologram quantitative structure–activity relationship (HQSAR) model and molecular docking on characterized binding sites followed by molecular dynamics (MD) simulations, which filtered a data set of 7.6 million compounds to 2,775 hits. Lastly, docking and MD simulations selected six final potential NS3 pro inhibitors with stable interactions along the simulations. Five compounds had their antiviral activity confirmed against ZIKV, YFV, DENV-2, and DENV-3 (ranging from 4.21 ± 0.14 to 37.51 ± 0.8 μM), displaying aggregator characteristics for enzymatic inhibition against ZIKV NS3 pro (ranging from 28 ± 7 to 70 ± 7 μM). Taken together, the compounds identified in this approach may contribute to the design of promising candidates to treat different flavivirus infections.