Methylations of tryptophan-modified naphthoquinone affect its inhibitory potential toward aβ aggregation

Roni Scherzer-Attali, Marino Convertino, Riccardo Pellarin, Ehud Gazit, Daniel Segal, Amedeo Caflisch

Research output: Contribution to journalArticlepeer-review

Abstract

Aggregation of amyloid beta (Aβ) is the hallmark of Alzheimer's disease (AD). Small molecules inhibiting Aβ can be valuable therapeutics for AD. We have previously reported that 1,4-naphthoquinon-2-yl-l-tryptophan (NQTrp), reduces aggregation and oligomerization of Aβ in vitro and in vivo. In silico analysis further showed that certain functional groups of NQTrp, not in the aromatic rings, are also involved in binding and inhibiting Aβ. To better understand the exact mode of action and identify the groups crucial for NQTrp inhibitory activity, we conducted structure-activity analysis. Four derivatives of NQTrp were studied in silico: a D-isomer, two single-methylated and one double-methylated derivative. In silico results showed that the NQTrp groups involved in hydrogen bonds are the anilinic NH (i.e., the NH linker between the quinone and tryptophan moieties), the quinonic carbonyls, and the carboxylic acid. These predictions were supported by in vitro results. Our results should aid in designing improved small-molecule inhibitors of Aβ aggregation for treating AD.

Original languageEnglish
Pages (from-to)1780-1789
Number of pages10
JournalJournal of Physical Chemistry B
Volume117
Issue number6
DOIs
StatePublished - 14 Feb 2013

Fingerprint

Dive into the research topics of 'Methylations of tryptophan-modified naphthoquinone affect its inhibitory potential toward aβ aggregation'. Together they form a unique fingerprint.

Cite this