Mechanisms of Metabolite Amyloid Formation: Computational Studies for Drug Design against Metabolic Disorders

Massimiliano Meli, Hamutal Engel, Dana Laor, Ehud Gazit, Giorgio Colombo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Ordered self-organization of polypeptides into fibrillar assemblies has been associated with a number of pathological conditions linked to degenerative diseases. Recent experimental observations have demonstrated that even small-molecule metabolites can aggregate into supramolecular arrangements with structural and functional properties reminiscent of peptide-based amyloids. The molecular determinants of such mechanisms, however, are not clear yet. Herein, we examine the process of formation of ordered aggregates by adenine in aqueous solution by molecular dynamics simulations. We also investigate the effects of an inhibiting polyphenol, namely, epigallocatechin gallate (EGCG), on this mechanism. We show that, while adenine alone is able to form extended amyloid-like oligomers, EGCG interferes with the supramolecular organization process. Interestingly, acetylsalicylic acid is shown not to interfere with ordered aggregation, consistent with experiments. The results of these mechanistic studies indicate the main pharmacophoric determinants that a drug-like inhibitor should possess to effectively interfere with metabolite amyloid formation.

Original languageEnglish
Pages (from-to)666-670
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume10
Issue number4
DOIs
StatePublished - 11 Apr 2019

Keywords

  • Self-organization
  • drug design
  • metabolic disorders
  • metabolites
  • molecular dynamics

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