Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

Receptors will not be further mentioned in this article because we focus on intracellular targets

Rona R. Ramsay; Magdalena Majekova; Milagros Medina; Massimo Valoti

2016

Scholarcy highlights

  • Neurodegeneration is a complex process that can arise from many different defects or insults
  • In the last century pharmacological research was driven to discover highly selective drugs. This strategy has failed, in part, because it is seen that the interaction with a single target, either receptor or enzyme, can promote compensatory adaptations in the living organisms leading to a failure of the therapy
  • These observations and the discovery that different pathologies have common aspects has led to the synthesis of new molecules that can interact with multiple targets with the aim to improved balance of efficacy and safety compared to single targeting drugs
  • We have reviewed the major targets for the assessment of multi-target designed ligands relevant to neurodegenerative diseases, giving examples of compounds generated by our collaborating medicinal chemists in COST Action CM1103
  • Mitochondria are highlighted as the area of future interest but the many possible targets will have to be refined to those most influential on progression in each specific disease
  • There are 18 mammalian cytochrome P450 isoenzymes, which encode 57 genes in the human genome. Of these CYP isoenzymes, more than 10 belong to the CYP1, 2, and 3 families and are responsible for the metabolism of more than 80% of xenobiotics and drugs used in therapy
  • When single target efficacy is achieved, new modalities can be added to MTDL for the ultimate prevention of neuropathology
  • When single target efficacy is achieved, new modalities can be added to multi-target designed ligands for the ultimate prevention of neuropathology

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