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

Abstract

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.

N-Benzyl Residues as the P1′ Substituents in Phosphorus-Containing Extended Transition State Analog Inhibitors of Metalloaminopeptidases

“…A few different benzaldehydes, namely halogen-containing (Cl, Br) or functionalized (COOH, NO 2 , NHAc, NMe 2 ) were selected as the precursors. According to the architecture of the aminopeptidase S′ pockets, which are hydrophobic clefts with functionalities located at the bottom [ 15 ], modifications in para position were mostly considered. The yield of N -benzylation was moderate, but separation straightforward—pure N-substituted glycines crystallized upon adjusting the appropriate pH.…”

Evaluation of the inhibitory potential of essential oils and aromatic extracts on SARS-CoV-2 Mpro and PLpro

“…The molecular modeling studies were prepared with the protocol of our earlier studies 47 . Crystal structures of the SARS-CoV-2 M pro (PDB ID: 6XBH -48 ) and SARS-CoV-2 PL pro (PDB ID: 6WX4 22 ) were obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB-PDB).…”

Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases

“…The substitution of the phenyl rings of phosphonic acid analogues of homophenylalanine with fluorine atoms only resulted in slightly better inhibitory potencies than compound 15a, which indicates a good acceptance of fluorine atoms by both enzymes. It is of some importance since compound 15a is quite commonly used as building block for the development of very potent aminopeptidase inhibitors [8]. Supplementation of the previously described set of phosphonic acid analogues of phenylalanine [10] had shown that they display lowest affinities towards the studied aminopeptidases.…”

“…The potential to affect many metabolic pathways, leading to incurable diseases, prompted the search for new-targeted therapies with the manipulation of APNs activities. Except for the commercially applied natural inhibitor of APN-bestatin, numerous scientific reports describe compounds with inhibitory properties towards aminopeptidases, based on the aminophosphonate scaffold [ 5 , 6 , 7 , 8 ]. However, none of them were introduced to clinical studies yet and thus the design of new potent and selective molecules is desirable.…”