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Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.

ABSTRACT: Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites. One antagonist is a competitive inhibitor that binds to the orthosteric site, while a second antagonist is a negative allosteric modulator that binds at a remote site. The allosteric modulator shows probe dependence, more effectively inhibiting peptide than protease activation of PAR2 signalling. Importantly, both antagonists are active in vivo, inhibiting PAR2 agonist-induced acute paw inflammation in rats and preventing activation of mast cells and neutrophils. These results highlight two distinct mechanisms of inhibition that potentially could be targeted for future development of drugs that modulate PAR2.

SUBMITTER: Kennedy AJ

PROVIDER: S-EPMC7747594 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.

Kennedy Amanda J AJ Sundström Linda L Geschwindner Stefan S Poon Eunice K Y EKY Jiang Yuhong Y Chen Rongfeng R Cooke Rob R Johnstone Shawn S Madin Andrew A Lim Junxian J Liu Qingqi Q Lohman Rink-Jan RJ Nordqvist Anneli A Fridén-Saxin Maria M Yang Wenzhen W Brown Dean G DG Fairlie David P DP Dekker Niek N

Communications biology 20201217 1

Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites. One antagonist is ...[more]

PMID: 33335291

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Project description:Allosteric modulators (AMs) are considered as a perpetual hotspot in research for their higher selectivity and various effects on orthosteric ligands (OL). They are classified in terms of their functionalities as positive, negative, or silent allosteric modulators (PAM, NAM, or SAM, respectively). In the present work, 11 pairs of three-dimensional (3D) structures of receptor-orthosteric ligand and receptor-orthosteric ligand-allosteric modulator complexes have been collected for the studies, including three different systems: GPCR, enzyme, and ion channel. Molecular dynamics (MD) simulations are applied to quantify the dynamic interactions in both the orthosteric and allosteric binding pockets and the structural fluctuation of the involved proteins. Our results showed that MD simulations of moderately large molecules or peptides undergo insignificant changes compared to crystal structure results. Furthermore, we also studied the conformational changes of receptors that bound with PAM and NAM, as well as the different allosteric binding sites in a receptor. There should be no preference for the position of the allosteric binding pocket after comparing the allosteric binding pockets of these three systems. Finally, we aligned four distinct β2 adrenoceptor structures and three N-methyl-d-aspartate receptor (NMDAR) structures to investigate conformational changes. In the β2 adrenoceptor systems, the aligned results revealed that transmembrane (TM) helices 1, 5, and 6 gradually increased outward movement from an enhanced inactive state to an improved active state. TM6 endured the most significant conformational changes (around 11 Å). For NMDAR, the bottom section of NMDAR's ligand-binding domain (LBD) experienced an upward and outward shift during the gradually activating process. In conclusion, our research provides insight into receptor-orthosteric ligand-allosteric modulator studies and the design and development of allosteric modulator drugs using MD simulation.

Dataset Information

Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.

Publications

Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.

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