2024-03-29T00:56:06Zhttps://www.tdx.cat/oai/requestoai:www.tdx.cat:10803/6715312024-03-15T10:57:34Zcom_10803_236col_10803_690278
nam a 5i 4500
Endogenous metabolome
Drug efficacy
Polypharmacology
Drug safety
Personalized medicine
Metaboloma endogen
Eficàcia dels fàrmacs
Polifarmacologia
Seguretat dels fàrmacs
Medicina personalitzada
The Impact of the human endogenous metabolome on drug pharmacology and safety
:
,
2021
Accés lliure
http://hdl.handle.net/10803/671531
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Bofill Pumarola, Andreu,
autor
Programa de doctorat en Biomedicina,
degree
1 recurs en línia (242 pàgines)
Tesi
Doctorat
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
2021
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
Tesis i dissertacions electròniques
Mestres i López, Jordi,
supervisor acadèmic
Jalencas i Giménez, Xavier,
supervisor acadèmic
TDX
A great deal of efforts has been made to improve and expand pharmacological testing and
optimisation of drug candidates during the discovery process. However, we are yet to
understand fully why drugs require certain levels of affinity for their mechanism of action
targets to exert their therapeutic effect. In parallel, the mechanistic understanding of the
endogenous metabolome has been demonstrated to have incredible implications in drug
discovery, being potentially one of the pillars of precision medicine. Endogenous
metabolites are small molecules evolutionally optimised to interact in an appropriate way
with its native protein with a specific level of affinity. This Thesis provides evidences that
the level of affinity required by a drug to interact with its primary target and produce a
therapeutic effect is related to the affinity of the native endogenous metabolite for that
target. In addition, this Thesis also highlights the implications that the human endogenous
metabolome could have to assess a more realistic drug polypharmacology landscape and
the risk of safety events linked to it. Finally, an analysis of natural compound
pharmacology on the perspective of the endogenous metabolome is also performed. All
results indicate that understanding the role of the human metabolome and its implications
on drug bioactivity could offer a new useful perspective in drug efficacy and safety
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