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P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases

Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
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Biomolecules 2020, 10(4), 659; https://doi.org/10.3390/biom10040659
Received: 20 March 2020 / Revised: 17 April 2020 / Accepted: 20 April 2020 / Published: 24 April 2020
Designing side chain substituents complementary to enzyme binding pockets is of great importance in the construction of potent and selective phosphinic dipeptide inhibitors of metallo-aminopeptidases. Proper structure selection makes inhibitor construction more economic, as the development process typically consists of multiple iterative preparation/bioassay steps. On the basis of these principles, using noncomplex computation and modeling methodologies, we comprehensively screened 900 commercial precursors of the P1′ residues of phosphinic dipeptide and dehydrodipeptide analogs to identify the most promising ligands of 52 metallo-dependent aminopeptidases with known crystal structures. The results revealed several nonproteinogenic residues with an improved energy of binding compared with the best known inhibitors. The data are discussed taking into account the selectivity and stereochemical implications of the enzymes. Using this approach, we were able to identify nontrivial structural elements substituting the recognized phosphinic peptidomimetic scaffold of metallo-aminopeptidase inhibitors. View Full-Text
Keywords: organophosphorus compounds; peptide analogs; enzyme inhibitors; ligand–enzyme interactions; molecular modeling and docking organophosphorus compounds; peptide analogs; enzyme inhibitors; ligand–enzyme interactions; molecular modeling and docking
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MDPI and ACS Style

Talma, M.; Mucha, A. P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases. Biomolecules 2020, 10, 659. https://doi.org/10.3390/biom10040659

AMA Style

Talma M, Mucha A. P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases. Biomolecules. 2020; 10(4):659. https://doi.org/10.3390/biom10040659

Chicago/Turabian Style

Talma, Michał; Mucha, Artur. 2020. "P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases" Biomolecules 10, no. 4: 659. https://doi.org/10.3390/biom10040659

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