Prolyl oligopeptidase (POP) is a protein that is over-expressed in many types of cancers such as epithelial cancer. It has also recently regained an interest for its involvement in α-synuclein aggregation, making it an interesting target for Parkinson’s disease (PD). Our development of covalent inhibitors against POP started in 2006 and was performed hand in hand with the development of our molecular docking platform Fitted. Because POP is a protease with a catalytically active serine residue, we decided to explore the avenue of covalent inhibition to target the key serine and achieve potency. With the help of Fitted, we have developed 5 chemical series with nitrile and boronic acid warheads which lead the identification of POP inhibitors with nanomolar potencies. In this presentation, we will describe our approach for the computer-aid identification, design and synthesis of these inhibitors as well as their evaluation as potential PD therapeutics.

Computer-aided drug design of prolyl oligopeptidase (POP) inhibitors

ACS Spring Meeting 2021

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