Binding modes of potential anti-prion phytochemicals to PrPC structures in silico

Background: Prion diseases involve the conversion of a normal, cell-surface glycoprotein (PrPC ) into a misfolded pathogenic form (PrPSC ). Cellular assays and in vivo experiments have identified various compounds with anti-prion activity which work through various mechanisms. Structures of PrPC have revealed the protein to occur in a swapped or non-swapped, monomeric or dimeric forms. Binding modes of known anti-prions is either not known, or has been determined with only the non-swapped structures of PrPC . In the current study medicinal phytochemicals from various databases have been docked with PrPC in silico to identify potential anti-prions in comparison with known anti-prion compounds to determine their binding modes and speculate possible mechanisms of inhibition of PrPC to PrPSC . 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 inhibition of PrPC to PrPSC conversion form interactions with most of the compounds. Conclusions: The new compounds are mostly highly hydrophobic and are derivatives of terpenes, sterols and quinones. They might act as potent inhibitors of the PrPC to PrPSC conversion through a combination of steric hindrance and stabilization of structure through ionic/hydrophobic interactions. Their high binding energies coupled with identical binding sites as those of the known compounds, and their ability to cross the blood brain barrier makes these phytochemicals a promising group of compounds for further studies on prevention of PrPC to PrPSC .