[Multifunctional ligands--a new approach in the search for drugs against multi-factorial diseases].
Selective drugs directed at a single biological target often prove ineffective in the treatment of diseases with a complex pathomechanism, e.g. Alzheimer's disease (AD). This situation prompts researchers to design multi-target-directed ligands (MTDLs), capable of interacting with a number of selected biological targets. The paper outlines the concept of the multi-target-directed ligand design and examples of its use in the search of a cure for AD. In the knowledge-based approach for designing MTDLs, selective ligands of different targets are combined in one molecule. In the screening-based approach, libraries of compounds are screened against selected targets, which allows one to find molecules with a desirable pharmacological profile. It is also possible to obtain multifunctional ligands by performing optimization of a drug with known side activity and transforming it into the main activity, with a simultaneous decrease or complete removal of the original activity. The type of biological targets and applied MTDL design strategy affect the physicochemical and pharmacokinetic properties of the resulting molecules. AD is a multifactorial neurodegenerative disease of the central nervous system associated with the formation of neurofibrillary tangles within neurons, formed by the hyperphosphorylated τ proteins, and extracellular β-amyloid deposits (senile plaques). Current AD therapy comprises symptomatic drugs that enhance cholinergic neurotransmission or inhibit glutamate receptors. The literature provides numerous examples of compounds which proved in in vitro tests to be multifunctional ligands. Most of them are derivatives of cholinesterase-inhibiting drugs, also capable of inhibiting the aggregation of Aβ and showing neuroprotective effects in Aβ-induced cytotoxicity assays.
Zakład Fizykochemicznej Analizy Leku Katedry Chemii Farmaceutycznej, Uniwersytet Jagielloński Collegium Medicum, Kraków.
Tomasz
T
Wichur
Zakład Fizykochemicznej Analizy Leku Katedry Chemii Farmaceutycznej, Uniwersytet Jagielloński Collegium Medicum, Kraków.
Barbara
B
Malawska
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D016874:Neurofibrillary Tangles; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D058225:Plaque, Amyloid; D016875:tau Proteins / Q000378:metabolism
D008024:Ligands; D018696:Neuroprotective Agents; D016875:tau Proteins