COMPUTATIONAL SCREENING OF POTENTIAL LIGANDS FOR THE METHYLTRANSFERASE DOMAIN OF HUMAN RESPIRATORY SYNCYTIAL VIRUS RNA POLYMERASE

The human Respiratory syncytial virus (hRSV) is a significant pathogen that primarily affects children under two years of age, causing severe lower respiratory tract diseases. It is also the leading cause of respiratory infections in the elderly and high-risk adults. Currently, the main clinical intervention is passive prophylaxis using the humanized monoclonal antibody palivizumab, helping to prevent hospitalization and severe hRSV infections in high-risk populations. However, its use is limited due to its high cost and modest efficacy. Therefore, urgent efforts are required to develop novel therapeutic agents against hRSV infections. This work aims to computationally identify potential antiviral candidates targeting the substrate and catalytic cofactor binding sites of the hRSV-RNA polymerase methyltransferase (MTase) domain. For this purpose, the crystal structure of the human Metapneumovirus (hMPV) MTase domain was used for homology modeling of the same hRSV domain, showing a highly conserved three-dimensional structure. Following that, analogous ligands to guanosine triphosphate (GTP) and S-adenosylmethionine (SAM), present at the substrate and catalytic cofactor sites, respectively, were virtually screened using molecular docking calculations. The next steps in this computational study involve conducting molecular dynamic simulations with the most promising GTP- and SAM-like ligands for evaluating their structural stability of the formed complexes with the hRSV MTase domain through parameters such as RMSD, hydrogen bonds, protein-ligand contacts, and binding-free energy. The outcomes of this project may significantly contribute to the search for effective strategies against hRSV infection.
This work was supported by Coordination for the Improvement of Higher Education Personnel (CAPES; process: 88887.670864/2022-00) and São Paulo Research Foundation (FAPESP; process 2022/13050-5; 2023/01632-2).