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Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors.

ABSTRACT: 4-Phenylbutanoyl-aminoacyl-2(S)-tetrazolylpyrrolidines were studied as prolyl oligopeptidase inhibitors. The compounds were more potent than expected from the assumption that the tetrazole would also here be a bioisostere of the carboxylic acid group and the corresponding carboxylic acids are at their best only weak inhibitors. The aminoacyl groups l-prolyl and l-alanyl gave potent inhibitors with IC₅₀ values of 12 and 129 nM, respectively. This was in line with typical prolyl oligopeptidase inhibitors; however, we did observe a difference with N-methyl-l-alanyl, which gave potent inhibitors in typical prolyl oligopeptidase inhibitors but not in our novel compound series. Furthermore, all studied 4-phenylbutanoyl-aminoacyl-2(S)-tetrazolylpyrrolidines decreased ?-synuclein dimerization at the concentration of 10 ?M, also when they were only weak inhibitors of the proteolytic activity of the enzyme with an IC₅₀ value of 205 ?M. Molecular docking studies revealed that the compounds are likely to bind differently to the enzyme compared to typical prolyl oligopeptidase inhibitors represented in this study by 4-phenylbutanoyl-aminoacyl-2(S)-cyanopyrrolidines.

SUBMITTER: Kilpelainen TP

PROVIDER: S-EPMC6912865 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors.

Kilpeläinen Tommi P TP Tyni Jonna K JK Lahtela-Kakkonen Maija K MK Eteläinen Tony S TS Myöhänen Timo T TT Wallén Erik A A EAA

ACS medicinal chemistry letters 20191111 12

4-Phenylbutanoyl-aminoacyl-2(<i>S</i>)-tetrazolylpyrrolidines were studied as prolyl oligopeptidase inhibitors. The compounds were more potent than expected from the assumption that the tetrazole would also here be a bioisostere of the carboxylic acid group and the corresponding carboxylic acids are at their best only weak inhibitors. The aminoacyl groups l-prolyl and l-alanyl gave potent inhibitors with IC<sub>50</sub> values of 12 and 129 nM, respectively. This was in line with typical prolyl ...[more]

PMID: 31857839

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Project description:Parkinson's disease is a common neurodegenerative disorder marked by the accumulation of the protein alpha synuclein. Studies have indicated the role of prolyl oligopeptidase (POP), a serine protease, in alpha synuclein accumulation. Therefore, POP emerges as an attractive medicinal target. Traditionally, most of the early medicines have been plant-based owing to their ready availability and negligible side effects. Alkaloids owing to their neurotransmitter modulatory, anti-amyloid, anti-oxidant, and anti-inflammatory activities have shown potential in neurodegenerative disease. In this work, we computationally evaluated alkaloid class of phytochemicals for their therapeutic efficacy against POP. Alkaloids were retrieved from the publically available database, Chemical Entities of Biological Interest (ChEBI), and screened for their drug likeness (Lipinski's rule of 5) and absorption, distribution, metabolism, and excretion, and toxicity (ADMET) in Discovery Studio by ensuring parameters suitable for a central nervous system disease such as blood-brain barrier (BBB) level set to ≤2, absorption level set to 0 and solubility level permitted set to 2, 3, or 4. Next, molecular docking was performed to learn about the affinity of the filtered alkaloids with the POP. Subsequently, molecular dynamic simulations were conducted to assess the reliability and stability of the alkaloid-protein complex. Our study identified metergoline, pipercallosine, celacinnine, lobeline, cystodytin G, lycoperine A, hookerianamide J, and martefragin A as putative lead compounds against POP. Among these, metergoline, pipercallosine, hookerianamide J, and lobeline showed the most promising results. These compounds demonstrated better or equivalent molecular docking scores in comparison to three POP inhibitors that had reached clinical trials, i.e., Z-321, S-17092, and JTP-4819. MD simulations indicated that these compounds remained intact at the active site while adhering to the binding mode and interaction patterns as that of the reported inhibitors. The research conducted here, therefore, provides evidence for conducting in vitro POP inhibitory studies of these newly identified plant-based POP inhibitors.

Dataset Information

Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors.

Publications

Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors.

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