Background: Alzheimer’s disease (AD) is considered a severe, irreversible and progressive
neurodegenerative disorder. Currently, the pharmacological management of AD is based on a
few clinically approved acethylcholinesterase (AChE) and N-methyl-D-aspartate (NMDA) receptor
ligands, with unclear molecular mechanisms and severe side effects.
Methods: Here, we reviewed the most recent bioinformatics, cheminformatics (SAR, drug design,
molecular docking, friendly databases, ADME-Tox) and experimental data on relevant structurebiological
activity relationships and molecular mechanisms of some natural and synthetic compounds
with possible anti-AD effects (inhibitors of AChE, NMDA receptors, beta-secretase, amyloid
beta (Aβ), redox metals) or acting on multiple AD targets at once. We considered: (i) in silico
supported by experimental studies regarding the pharmacological potential of natural compounds as
resveratrol, natural alkaloids, flavonoids isolated from various plants and donepezil, galantamine,
rivastagmine and memantine derivatives, (ii) the most important pharmacokinetic descriptors of
natural compounds in comparison with donepezil, memantine and galantamine.
Results: In silico and experimental methods applied to synthetic compounds led to the identification
of new AChE inhibitors, NMDA antagonists, multipotent hybrids targeting different AD processes
and metal-organic compounds acting as Aβ inhibitors. Natural compounds appear as multipotent
agents, acting on several AD pathways: cholinesterases, NMDA receptors, secretases or Aβ, but
their efficiency in vivo and their correct dosage should be determined.
Conclusion: Bioinformatics, cheminformatics and ADME-Tox methods can be very helpful in the
quest for an effective anti-AD treatment, allowing the identification of novel drugs, enhancing the
druggability of molecular targets and providing a deeper understanding of AD pathological mechanisms.