Τίτλος:
Dual A1/A3 Adenosine Receptor Antagonists: Binding Kinetics and Structure-Activity Relationship Studies Using Mutagenesis and Alchemical Binding Free Energy Calculations
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Drugs targeting adenosine receptors (AR) can provide treatment for diseases. We report the identification of 7-(phenylamino)-pyrazolo[3,4-c]pyridines L2-L10, A15, and A17 as low-micromolar to low-nanomolar A1R/A3R dual antagonists, with 3-phenyl-5-cyano-7-(trimethoxyphenylamino)-pyrazolo[3,4-c]pyridine (A17) displaying the highest affinity at both receptors with a long residence time of binding, as determined using a NanoBRET-based assay. Two binding orientations of A17 produce stable complexes inside the orthosteric binding area of A1R in molecular dynamics (MD) simulations, and we selected the most plausible orientation based on the agreement with alanine mutagenesis supported by affinity experiments. Interestingly, for drug design purposes, the mutation of L2506.51 to alanine increased the binding affinity of A17 at A1R. We explored the structure-activity relationships against A1R using alchemical binding free energy calculations with the thermodynamic integration coupled with the MD simulation (TI/MD) method, applied on the whole G-protein-coupled receptor-membrane system, which showed a good agreement (r = 0.73) between calculated and experimental relative binding free energies. © 2022 American Chemical Society.
Συγγραφείς:
Stampelou, M.
Suchankova, A.
Tzortzini, E.
Dhingra, L.
Barkan, K.
Lougiakis, N.
Marakos, P.
Pouli, N.
Ladds, G.
Kolocouris, A.
Περιοδικό:
Journal of Medicinal Chemistry
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
3 phenyl 5 cyano 7 (trimethoxyphenylamino)pyrazolo[3,4 c]pyridine; 9 chloro 2 (2 furyl) 5 phenylacetylamino 1,2,4 triazolo[1,5 c]quinazoline; adenosine 5' (n ethylcarboxamide); adenosine A1 receptor; adenosine A1 receptor antagonist; adenosine A3 receptor; adenosine A3 receptor antagonist; alanine; aniline derivative; cyclic AMP; G protein coupled receptor; pyrrolo[3,4 c]pyridine derivative; unclassified drug; adenosine A1 receptor; adenosine A2a receptor; adenosine A3 receptor; adenosine A3 receptor antagonist; adenosine receptor blocking agent; pyridine derivative, animal cell; Article; binding affinity; binding kinetics; calculation; competitive binding assay; complex formation; concentration response; controlled study; drug binding site; drug design; drug potency; drug receptor binding; drug screening; energy; human; human cell; ligand binding; molecular docking; molecular dynamics; molecular interaction; molecular stability; mutagenesis; mutation; nonhuman; pharmacophore; receptor affinity; structure activity relation; thermodynamics; chemistry; genetics; metabolism; mutagenesis; structure activity relation, Adenosine A3 Receptor Antagonists; Alanine; Mutagenesis; Purinergic P1 Receptor Antagonists; Pyridines; Receptor, Adenosine A1; Receptor, Adenosine A2A; Receptor, Adenosine A3; Structure-Activity Relationship
DOI:
10.1021/acs.jmedchem.2c01123
