In silico search for an endogenous anti-Alzheimer’s molecule — Screening amino acid metabolic pathways

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder arising from abnormal aggregation of β-amyloid (Aβ) and progressing at different rates from person to person. There may exist endogenous compounds within the brain that play a role in inhibiting aggregation. We have devised a unique in silico screening strategy of endogenous molecules within the human brain, with special emphasis on amino acid metabolic pathways, to identify compounds with the potential to inhibit Aβ aggregation. Metabolites of tryptophan were computationally identified through this screening as potential therapeutics and were optimized via molecular modelling to determine their capacity to bind to Aβ. The most successful molecule identified was 3-hydroxyanthranilic acid (3-HAA). This endogenous molecule was then computationally explored to design novel analogues of 3-HAA with the goal of improving Aβ antiaggregant activity. These combined in silico methods of screening, identifying, and successfully “analoguing” an endogenous molecule of the brain as an AD therapeutic has yielded positive results and a novel approach to computer-aided drug design.