Identification of Potential Inhibitors against the Human Influenza A Virus Targeting the CPSF30 and RNA Binding Domains of the NS1 Protein: An E-Pharmacophore approach.

Abstract:

Background: Common occurrences of influenza virus strains resistant to known neuraminidase and matrix protein inhibitors like oseltamivir and amantadine respectively necessitate the development of newer antivirals. The virus’ non-structural protein (NS1) through its effector domain (ED) and RNA binding domain (RBD) plays significant roles in overcoming the host antiviral response and regulating the virus replication cycle respectively. Aim: This work attempts to identify potential NS1 based inhibitors against influenza, by interrupting the above stated mechanisms through using insilico drug design methods. Methods: E-pharmacophore models, were generated by docking a fragment library at the active sites of both the domains using GlideXP. Based on the energyoptimized pharmacophore obtained, the Phase program was used to screen Asinex’s MedChem building blocks to find suitable hits with the essential pharmacophore features. Results: The docking complexes of the top ranking compounds at the ED formed hydrogen bond contacts with Gly184, Asn188, and hydrophobic contacts with Ile119, Trp187 which are critical for binding the F3 zinc finger of the cleavage and polyadenylation specificity factor (CPSF30). The top ranking compounds at the RBD made hydrogen bond contacts with critical residues Arg38 of both its chains and showed better docking score and space occupancy when compared to the top ranking compounds at the ED. Conclusion: The compounds identified and their backbone structural scaffolds could be further used to design drug like compounds targeting the NS1 protein of influenza. Further invitro studies would be required for testing their antiviral activity as well as for ligand optimization.

Key words: Influenza, Non structural (NS1) protein, Molecular docking, E-pharmacophore mapping, Virtual screening.