Binding modes of potential anti-prion phytochemicals to PrP(C) structures in silico

BACKGROUND: Prion diseases involve the conversion of a normal, cell-surface glycoprotein (PrP(C)) into a misfolded pathogenic form (PrP(Sc)). One possible strategy to inhibit PrP(Sc) formation is to stabilize the native conformation of PrP(C) and interfere with the conversion of PrP(C) to PrP(Sc). Many compounds have been shown to inhibit the conversion process, however, no promising drugs have been identified to cure prion diseases. OBJECTIVE: This study aims to identify potential anti-prion compounds from plant phytochemicals by integrating traditional ethnobotanical knowledge with modern in silico drug design approaches. MATERIALS AND METHODS: In the current study medicinal phytochemicals were docked with swapped and non-swapped crystal structures of PrP(C)in silico to identify potential anti-prions to determine their binding modes and interactions. RESULTS: Eleven new phytochemicals were identified based on their binding energies and pharmacokinetic properties. The binding sites and interactions of the known and new anti-prion compounds are similar, and differences in binding modes occur in structures with very subtle differences in side chain conformations. Binding of these compounds poses steric hindrance to neighbouring molecules. Residues shown to be associated with the inhibition of PrP(C) to PrP(Sc) conversion form interactions with most of the compounds. CONCLUSION: Identified compounds might act as potent inhibitors of PrP(C) to PrP(Sc) conversion. These might be attractive candidates for the development of novel anti-prion therapy although further tests in vitro cell cultures and in vivo mouse models are needed to confirm these findings.