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

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 4; p. 659
• Main Authors: Talma, Michał, Mucha, Artur
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-04-2020; MDPI
• Subjects: Algorithms; Amino acids; Aminopeptidase; Aminopeptidases - antagonists & inhibitors; Analysis; Binding Sites; Dipeptides - analysis; Dipeptides - chemistry; Dipeptides - pharmacology; Drug Evaluation, Preclinical; Enzyme inhibitors; Enzyme Inhibitors - analysis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Humans; Identification and classification; Ligands; ligand–enzyme interactions; Models, Molecular; Molecular Docking Simulation; molecular modeling and docking; Optimization; Organometallic compounds; organophosphorus compounds; peptide analogs; Peptides; Phosphoric acid; Proteins; Studies; User-Computer Interface; Poland; organophosphorus compounds; ligand–enzyme interactions; peptide analogs; enzyme inhibitors; molecular modeling and docking
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10040659

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.