Multisite Model of Allosterism for the Adenosine A1 Receptor

Abstract

Despite being a target for about one-third of approved drugs, G protein-coupled receptors (GPCRs) still represent a tremendous reservoir for therapeutic strategies against countless diseases. For example, several cardiovascular and central nervous systems conditions could benefit from clinical agents that activate the adenosine 1 receptor (A 1 R), however, the pursuit of A 1 R agonists for clinical use are usually impeded by both on-and off-target side effects. One of the possible strategies to overcome this issue is the development of positive allosteric modulators (PAMs) capable of selectively enhancing the effect of a specific receptor subtype and triggering functional selectivity (a phenomenon also referred to as bias). Intriguingly, besides enforcing the effect of agonists upon binding to an allosteric site, most of the A 1 R PAMs display intrinsic partial agonism and orthosteric competition with antagonists. To rationalize this behaviour, we simulated the binding of the prototypical PAMs PD81723 and VCP171, the antagonist 13B, and the bitopic agonist VCP746. We propose that a single PAM can bind several A 1 R sites rather than a unique allosteric pocket, reconciling the structure-activity relationship and the mutagenesis results.

Molecular Simulations and Drug Discovery of Adenosine Receptors

“…Remarkable advances in MD approaches and computer hardware have paved the way to capture the ligand binding/unbinding processes of ARs in molecular details [ 166 ], which is expected to play a more important role in drug design in the future. In this context, advanced computational platforms (e.g., ANTON 3 [ 167 ] and Deep Docking [ 168 ]) and improved simulation techniques, including the coarse-grained MD, FEP, ligand and peptide GaMD [ 169 , 170 ], SuMD [ 110 ], Metadynamics [ 93 ], machine learning [ 171 ] and deep learning [ 168 , 172 , 173 ], will continue to drive rational computer-aided design of more potent and selective drug molecules of ARs.…”

“…In previous studies, bitopic ligands that comprise of orthosteric and allosteric ligand binding moieties were shown to exhibit biased agonism in the A 1 AR [ 100 , 109 ]. The supervised MD (SuMD) simulations were performed to capture the binding of bitopic agonist VCP746 (biased agonist) and its allosteric part (VCP171) to the A 1 AR [ 110 ]. The VCP746 sampled the most stable binding pose when the orthosteric site was occupied by the adenosine moiety, suggesting that the agonist component of the VCP746 played a particularly important role in the binding.…”

“…However, the TM helices rearranged to accommodate the sodium ion in an intermediate-active state of A 2A AR. Deganutti et al performed SuMD simulations to capture binding of the antagonist 13B, bitopic agonist VCP746 and PAMs PD81723 and VCP171 to the A 1 AR [ 110 ]. The SuMD simulations showed that PAMs can bind to several receptor sites rather than a single allosteric pocket.…”

“…Valant et al [ 109 ] combined the endogenous agonist and allosteric modulator to design a bitopic ligand VCP746 as a biased agonist of A 1 AR that favored cAMP pathway over ERK1/2 phosphorylation pathway. Molecular docking calculations and SuMD simulations [ 110 , 154 ] were used to study ligand binding to the receptor (see Section 3.4 ).…”

“…Docking calculations using the A 1 AR homology model suggested that the allosteric and linker region of the bitopic ligand explored the extracellular vestibule of the receptor. Deganutti et al [ 110 ] applied SuMD to simulate the binding of VCP746 to A 1 AR and proposed the binding modes of the bitopic ligand. The adenosine moiety of the ligand bound stably at the orthosteric site, whereas the VCP171 part bound near the ECL2 region.…”