Extrahelical Binding Site for a 1 H -Imidazo[4,5-c]quinolin-4-amine A 3 Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7.

Autor: Fisher CL; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)., Pavan M; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)., Salmaso V; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)., Keyes RF; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)., Wan TC; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)., Pradhan B; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)., Gao ZG; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)., Smith BC; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)., Jacobson KA; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.) jauchamp@mcw.edu kennethj@niddk.nih.gov., Auchampach JA; Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.) jauchamp@mcw.edu kennethj@niddk.nih.gov.
Jazyk: angličtina
Zdroj: Molecular pharmacology [Mol Pharmacol] 2024 Feb 15; Vol. 105 (3), pp. 213-223. Date of Electronic Publication: 2024 Feb 15.
DOI: 10.1124/molpharm.123.000784
Abstrakt: This study describes the localization and computational prediction of a binding site for the A 3 adenosine receptor (A 3 AR) positive allosteric modulator 2-cyclohexyl-1 H -imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H) 8, which was predicted by molecular modeling and validated by mutagenesis. According to the model, the nearly planar 1 H -imidazo[4,5-c]quinolinamine ring system lies parallel to the transmembrane segments, inserted into an aromatic cage formed by π-π stacking interactions with the side chains of Y284 7.55 in TMD7 and Y293 8.54 in H8 and by π-NH bonding between Y284 7.55 and the exocyclic amine. The 2-cyclohexyl group is positioned "upward" within a small hydrophobic subpocket created by residues in TMDs 1 and 7, while the 3,4-dichlorophenyl group extends toward the lipid interface. An H-bond between the N - 1 amine of the heterocycle and the carbonyl of G29 1.49 further stabilizes the interaction. Molecular dynamics simulations predicted two metastable intermediates, one resembling a pose determined by molecular docking and a second involving transient interactions with Y293 8.54 ; in simulations, each of these intermediates converges into the final bound state. Structure-activity-relationships for replacement of either of the identified exocyclic or endocyclic amines with heteroatoms lacking H-bond donating ability were consistent with the hypothetical pose. Thus, we characterized an allosteric pocket for 1 H -imidazo[4,5-c]quinolin-4-amines that is consistent with data generated by orthogonal methods, which will aid in the rational design of improved A 3 AR positive allosteric modulators. SIGNIFICANCE STATEMENT: Orthosteric A 3 AR agonists have advanced in clinical trials for inflammatory conditions, liver diseases, and cancer. Thus, the clinical appeal of selective receptor activation could extend to allosteric enhancers, which would induce site- and time-specific activation in the affected tissue. By identifying the allosteric site for known positive allosteric modulators, structure-based drug discovery modalities can be enabled to enhance the pharmacological properties of the 1 H -imidazo[4,5-c]quinolin-4-amine class of A 3 AR positive allosteric modulators.
(U.S. Government work not protected by U.S. copyright.)
Databáze: MEDLINE
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