Computational Study on Conus Textile Conopeptides for Mediating Ion Channel Transport

The lengthy, complex, and costly process enclosed with a high degree of uncertainty that a drug will gain market approval are challenges in drug discovery and development. With high-throughput screening and computational methods, computer-aided drug discovery can accelerate the lengthy and costly processes. The predatory cone snails of the genus Conus are specialists in neuropharmacology. In the Philippines, C. textile is reported to inhabit the tropical waters of the islands. Their conopeptide-rich venom can serve as repertoires of potential drug candidates for distinct diseases. Although isolation and activity studies have been conducted, most are tested in animal models only, and there are important distinctions between a human patient and animal prey. To investigate their human therapeutics application, we acquired the 3D structures of the conopeptides, target receptors, natural ligands, and FDA-approved drugs. We conducted a binding affinity and ligand-receptor interaction analysis. Results showed that Conorfamide Tx-1, Contryphan TxR, alpha-conotoxin TxIA, and epsilon-conotoxin TxVA have superior binding affinity compared to the target receptor's endogenous and FDA-approved drug ligand. However, conopressin and delta-conotoxin TxVIA have lower binding affinities than the positive controls. Important key residue interactions that affect binding affinities were identified that can guide future studies in peptide modification.