Tau-Derived-Hexapeptide 306VQIVYK311 Aggregation Inhibitors: Nitrocatechol Moiety As A Pharmacophore In Drug Design.

ACS chemical neuroscience

PubMedID: 24007550

Mohamed T, Hoang T, Jelokhani-Niaraki M, Rao PP. Tau-Derived-Hexapeptide 306VQIVYK311 Aggregation Inhibitors: Nitrocatechol Moiety As A Pharmacophore In Drug Design. ACS Chem Neurosci. 2013;.
The nitrocatechol derivatives tolcapone (1) and entacapone (2), used as adjunctive therapy in the treatment of Parkinson's disease, were investigated for their potential to inhibit the tau-derived-hexapeptide 306VQIVYK311. They were compared to small molecules that contain similar pharmacophores including the catechol derivatives (dopamine 3 and epinephrine 4), nitroderivatives (nifedipine 5 and chloramphenicol 6), nitrocatechol isomers (7 and 8) and a tolcapone derivative (13) lacking the nitrocatechol moiety. The aggregation kinetics by thioflavin S fluorescence assay indicates that both tolcapone (1) and entacapone (2) exhibit anti-aggregation properties. These findings were supported by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy measurements which suggest that the nitrocatechol (3,4-dihydroxy-5-nitrophenyl) moiety is a suitable pharmacophore in the design of new tau-aggregation inhibitors. Furthermore, tolcapone (1) was identified as most active compound with anti-aggregation activity (46% inhibition of fluorescence intensity at 50 µM), which was supported by TEM data. The in silico steric zipper model of the tau-derived-hexapeptide 306VQIVYK311 indicates that the 3,4-dihydroxy-substituent present in tolcapone (1) and entacapone (2) underwent polar contacts with lysine side chains (VQIVYK), whereas the charged 5-nitrosubstituent was in close contact with lysine side chain present in the steric zipper region suggesting the critical role of a nitrocatechol (3,4-dihydroxy-5-nitrophenyl) pharmacophore present in tolcapone (1) and entacapone (2) in tau-hexapeptide binding and prevention of ß-sheet assembly. Our results have significant implications in the design and development of tau-aggregation inhibitors.