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

6533b861fe1ef96bd12c5a76

RESEARCH PRODUCT

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

Paweł Kafarski Błażej Dziuk Błażej Dziuk Michał Talma Weronika Wanat

subject

Models Molecular Protein Conformation alpha-Helical Molecular model Stereochemistry Phosphorous Acids Swine Phenylalanine lcsh:QR1-502 Phenylalanine CD13 Antigens computer-aided simulations Inhibitory postsynaptic potential 01 natural sciences Biochemistry lcsh:Microbiology Article Phenylalanine derivatives Substrate Specificity Small Molecule Libraries 03 medical and health sciences Structure-Activity Relationship Animals Humans Protein Interaction Domains and Motifs Enzyme Inhibitors phosphonic acid inhibitors Molecular Biology 030304 developmental biology Alanine chemistry.chemical_classification 0303 health sciences Inhibitory potential Binding Sites 010405 organic chemistry Chemistry Aminobutyrates Fluorine Bromine 0104 chemical sciences Isoenzymes Kinetics Enzyme human and porcine alanine aminopeptidase fluorine and bromine substitution Thermodynamics Protein Conformation beta-Strand Protein Binding

description

A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.

year	journal	country	edition	language
2020-09-14	Biomolecules

10.3390/biom10091319 https://pubmed.ncbi.nlm.nih.gov/32938014