Host-Directed Anti-Fusion Aptamers and Small Molecules as Respiratory Syncytial Virus (RSV) Inhibitors: An in silico-based study

Author(s): Ssemuyiga Charles, Mulumba Pius Edgar, Rajani Kanta Mahapatra

Despite significant medical advancements, RSV continues to strain healthcare systems and society. For over 60 years, developing a vaccine for RSV has been a top priority. In 2023, a milestone of two vaccines of Abrysvo and Arexvy were introduced 1. The physical interactions between Nucleolin (NCL) RBD1,2 and RSV-F protein during virus entry were identified by peptide arrays as two antiparallel strands of β-sheet in RBD1. We screened for novel ligands targeting NCL to inhibit this particular interaction. In a nutshell, small molecule inhibitors and nucleic acid aptamers were specifically docked to NCL RBD1, 2 targeting the previously identified strands. A total of 528 aptamers were docked to NCL RBD1,2 on the HDOCK website; the top 180 aptamers with docking scores equal to or better than -200 were then re-docked at the HADDOCK website, and the top 58 aptamers were chosen. Additionally, 976,450 small molecules were docked using Schrodinger Virtual Screening Workflow, and the top 50 ligands underwent post-docking validation using Prime MM_GBSA. The 16 best ligands were chosen from the top 30 using binding affinity from Molegro Virtual Docker. For molecular simulation dynamics studies, four protein-ligand complexes and six protein-aptamer complexes were randomly chosen and the results were analyzed. The results show that the selected NCL ligands are potential NCL binders and can inhibit NCL-RSV-F interactions. Results suggest that aptamers are better binders than small molecules. BDBM50308336, 1exd, and 5uza formed the most stable complexes. With many benefits as host-directed therapeutics, these ligands need in-vitro testing for potential inhibition of RSV entry besides some probable drawbacks.