Finding Drugs for Poxviruses: Targeting the L1 Protein

This study computationally compares natural compounds and synthetic drugs, particularly antivirals, against known and novel protein targets of Poxviruses using Cresset Flare(computational software). While several antiviral drugs have exhibited in vitro anti-poxvirus activity, cidofovir, a nucleoside analog approved for cytomegalovirus retinitis treatment in AIDS, has shown limited therapeutic utility due to its significant nephrotoxicity. The following computational approaches were employed: • Ligand-based screening: Using cidofovir as a reference, a library of approximately 3000 natural compounds and common drugs, as well as a library of 700 antiviral molecules, were screened. • Structure-based screening: A co-crystallized cidofovir-protein complex (PDB ID 5KM8) was used as a template to screen a library of natural compounds. • Protein-protein docking: S. pneumoniae topoisomerases, for which drug-bound structures are available, were aligned with topoisomerases lacking ligands to identify potential binding sites. • Covalent docking: Serine and tyrosine residues within hydrophobic pockets were targeted with drugs and natural compounds containing nitrile groups. The poxvirus L1 protein, a conserved target across the poxvirus family, presents a myristoylated envelope protein with a hydrophobic cavity. This cavity is essential for virion assembly and represents a potential target for antibody-based therapies and vaccine development [5]. By identifying potential inhibitors for these critical poxvirus targets, this study aims to contribute to the development of novel antiviral strategies.