Pharmacophore-based models for therapeutic drugs against phosphorylated tau in Alzheimer's disease

Drug Discov Today. 2019 Feb;24(2):616-623. doi: 10.1016/j.drudis.2018.11.005. Epub 2018 Nov 16.

Abstract

Phosphorylated tau (P-tau) has received much attention in the field of Alzheimer's disease (AD), as a potential therapeutic target owing to its involvement with synaptic damage and neuronal dysfunction. The continuous failure of amyloid β (Aβ)-targeted therapeutics highlights the urgency to consider alternative therapeutic strategies for AD. The present review describes the latest developments in tau biology and function. It also explains abnormal interactions between P-tau with Aβ and the mitochondrial fission protein Drp1, leading to excessive mitochondrial fragmentation and synaptic damage in AD neurons. This article also addresses 3D pharmacophore-based drug models designed to treat patients with AD and other tauopathies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Dynamins
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Microtubule-Associated Proteins / metabolism
  • Microtubules
  • Mitochondrial Proteins / metabolism
  • Models, Biological*
  • Neuroprotective Agents / therapeutic use*
  • Phosphorylation
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Neuroprotective Agents
  • tau Proteins
  • GTP Phosphohydrolases
  • DNM1L protein, human
  • Dynamins