1212092-04-0Relevant articles and documents
Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α
Plescia, Jessica,De Cesco, Stéphane,Patrascu, Mihai Burai,Kurian, Jerry,Di Trani, Justin,Dufresne, Caroline,Wahba, Alexander S.,Janmamode, Na?la,Mittermaier, Anthony K.,Moitessier, Nicolas
, p. 7874 - 7884 (2019/10/11)
Over the past decade, there has been increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein α (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity toward electrophilic warheads. To streamline such investigations, we exploited both computational and experimental methods to investigate the influence of different reactive groups on both potency and binding kinetics using both our own series of POP inhibitors and others' discovered hits. A direct correlation between inhibitor reactivity and residence time was demonstrated through quantum mechanics methods and further supported by experimental studies. This computational method was also successfully applied to FAP, as an overview of known FAP inhibitors confirmed our computational predictions that more reactive warheads (e.g., boronic acids) must be employed to inhibit FAP than for POP.
Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells
De Cesco, Stéphane,Deslandes, Sébastien,Therrien, Eric,Levan, David,Cueto, Micka?l,Schmidt, Ralf,Cantin, Louis-David,Mittermaier, Anthony,Juillerat-Jeanneret, Lucienne,Moitessier, Nicolas
, p. 6306 - 6315 (2012/09/22)
Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one-five chemical steps. Biological evaluations on recombinant POP and FAPα enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAPα and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.
