Favipiravir Analogues As Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase, Combined Quantum Chemical Modeling, Quantitative Structure-Property Relationship, and Molecular Docking Study

Our study was motivated by the urgent need to develop or improve antivirals for effective therapy targeting RNA viruses. We hypothesized that analogues of favipiravir (FVP), an inhibitor of RNA-dependent RNA polymerase (RdRp), could provide more effective nucleic acid recognition and binding processes while reducing side effects such as cardiotoxicity, hepatotoxicity, teratogenicity, and embryotoxicity. We proposed a set of FVP analogues together with their forms of triphosphate as new SARS-CoV-2 RdRp inhibitors. The main aim of our study was to investigate changes in the mechanism and binding capacity resulting from these modifications. Using three different approaches, QTAIM, QSPR, and MD, the differences in the reactivity, toxicity, binding efficiency, and ability to be incorporated by RdRp were assessed. Two new quantum chemical reactivity descriptors, the relative electro-donating and electro-accepting power, were defined and successfully applied. Moreover, a new quantitative method for comparing binding modes was developed based on mathematical metrics and an atypical radar plot. These methods provide deep insight into the set of desirable properties responsible for inhibiting RdRp, allowing ligands to be conveniently screened. The proposed modification of the FVP structure seems to improve its binding ability and enhance the productive mode of binding. In particular, two of the FVP analogues (the trifluoro- and cyano-) bind very strongly to the RNA template, RNA primer, cofactors, and RdRp, and thus may constitute a very good alternative to FVP.