Computational Evaluation of Binding Properties for Covalent Ligands in Prolyl Oligopeptidase and Fibroblast Activation Protein

Download or read book Computational Evaluation of Binding Properties for Covalent Ligands in Prolyl Oligopeptidase and Fibroblast Activation Protein written by Jerry Kurian and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Over the past decade, an increasing interest for covalent inhibition - modulating enzyme activity through covalently binding to it - as a drug design strategy has been observed. To aid in the development of covalent inhibitors, techniques which allow for prediction and characterization of activity must be made available. Knowledge about covalent inhibitor strength, activation energies, residence times and mechanisms must be obtained to allow for successful covalent drug development methodologies. In this thesis, we assessed whether two serine proteases, prolyl oligopeptidase (POP) and fibroblast activation protein (FAP), react similarly with respect to kinetics and thermodynamics in relation to the electrophile on the covalent ligand. To streamline such investigations, we exploited computational techniques as a method for prediction of covalent druggability - the ability of an enzyme to be inhibited through covalent means. We investigated the influence of different electrophilic groups (aldehyde, boronic acid and nitrile) on potency and binding kinetics with a series of truncated analogous inhibitors of POP, using quantum mechanical (QM) methods, such as the quantum chemical cluster approach (QCCA). The direct correlation between inhibitor reactivity and residence time was demonstrated through the QCCA and was further supported by experimental studies in the Moitessier group. The validated computational method was then applied to FAP, which has previously been thought to be less reactive than POP. Computations in this work predicted that the truncated ligands binding to POP result in a larger energy lowering compared to FAP. Similar computational techniques were used to evaluate the atomic basis for this difference in reactivity through a detailed analysis of hydrogen bond lengths and angles in the active site of POP. This analysis was supplemented with calculations on the difference in basicity of the catalytic histidine in POP and FAP, responsible for removing the proton off the catalytic serine. The stronger the base, the easier the catalytic serine residue can be deprotonated and hence more reactive and available for nucleophilic attack. The data suggests that the histidine in POP may be more basic than in FAP, supporting the claim that the serine in POP may be more reactive than in FAP." --