4BCB

PROLYL OLIGOPEPTIDASE FROM PORCINE BRAIN WITH A COVALENTLY BOUND P2- substituted N-acyl-prolylpyrrolidine inhibitor

Summary for 4BCB

• Entry DOI: 10.2210/pdb4bcb/pdb
• Related: 1E5T 1E8M 1E8N 1H2W 1H2X 1H2Y 1H2Z 1O6F 1O6G 1QFM 1QFS 1UOO 1UOP 1UOQ 1VZ2 1VZ3 2XDW 4AMY 4AMZ 4AN0 4AN1 4AX4 4BCC 4BCD
• Related PRD ID: PRD_002042
• Descriptor: PROLYL ENDOPEPTIDASE, (5R,6R,8S)-8-(3-{[AMINO(IMINO)METHYL]AMINO}PHENYL)-5-CYCLOHEXYL-6-HYDROXY-3-OXO-1-PHENYL-2,7-DIOXA-4-AZA-6-PHOSPHANONAN-9-OIC ACID 6-OXIDE, TRIS(HYDROXYETHYL)AMINOMETHANE, ... (5 entities in total)
• Functional Keywords: alpha-beta-hydrolase, amnesia, beta-propeller, hydrolase, parkinsons disease, alzheimers disease
• Biological source: SUS SCROFA (PIG)
• Cellular location: Cytoplasm: P23687
• Total number of polymer chains: 1
• Total formula weight: 82255.87

Authors

VanDerVeken, P.,Fulop, V.,Rea, D.,Gerard, M.,VanElzen, R.,Joossens, J.,Cheng, J.D.,Baekelandt, V.,DeMeester, I.,Lambeir, A.M.,Augustyns, K. (deposition date: 2012-10-01, release date: 2013-03-13, Last modification date: 2024-10-23)

Primary citation

Van Der Veken, P.,Fulop, V.,Rea, D.,Gerard, M.,Van Elzen, R.,Joossens, J.,Cheng, J.D.,Baekelandt, V.,De Meester, I.,Lambeir, A.M.,Augustyns, K.
P2-Substituted N-Acylprolylpyrrolidine Inhibitors of Prolyl Oligopeptidase: Biochemical Evaluation, Binding Mode Determination, and Assessment in a Cellular Model of Synucleinopathy.
J.Med.Chem., 55:9856-, 2012

PubMed Abstract: We have investigated the effect of regiospecifically introducing substituents in the P2 part of the typical dipeptide derived basic structure of PREP inhibitors. This hitherto unexplored modification type can be used to improve target affinity, selectivity, and physicochemical parameters in drug discovery programs focusing on PREP inhibitors. Biochemical evaluation of the produced inhibitors identified several substituent types that significantly increase target affinity, thereby reducing the need for an electrophilic "warhead" functionality. Pronounced PREP specificity within the group of Clan SC proteases was generally observed. Omission of the P1 electrophilic function did not affect the overall binding mode of three representative compounds, as studied by X-ray crystallography, while the P2 substituents were demonstrated to be accommodated in a cavity of PREP that, to date, has not been probed by inhibitors. Finally, we report on results of selected inhibitors in a SH-SY5Y cellular model of synucleinopathy and demonstrate a significant antiaggregation effect on α-synuclein.

PubMed: 23121075
DOI: 10.1021/JM301060G

Experimental method

X-RAY DIFFRACTION (1.7 Å)