Monopharmacology, polypharmacology and PROTAC approaches in drug discovery: investigation of enzyme inhibitors and antioxidant compounds

MOI, DAVIDE

2020-02-06

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Abstract

Nowadays the better understanding of pathological mechanisms is strongly correlated with the evolution of drug discovery: new targets have been validated and new strategies have been performed. The approach based on the direct relationship between a specific protein and the resulting phenotype, called “monopharmacology” resulted fundamental over the years for the developing of commercial drugs and it is still used in drug discovery to develop selective enzymatic inhibitors. Progress in biology studies demonstrated that the traditional approach is limited, so that designing a single drug acting simultaneously on different targets may be a better solution. This approach called “polypharmacology” refers to a single drug which acts simultaneously on two or more targets, achieving additively or synergistically activity. A further evolution of drug discovery is the Proteolysis-Targeting Chimeras (PROTACs), heterobifunctional molecules, constituted by a small molecule inhibitor linked to a ligand for an E3 ligase and offer a different method in drug discovery: the protein target is not just “inhibited”, but it is eliminated via the cells own proteasomal machinery. This thesis describes the design, synthesis and biological activity of compounds using the above described three different approaches in drug discovery.​