Pharmacological Targeting of AMP-Activated Protein Kinase and Opportunities for Computer-Aided Drug Design

Abstract

As a central regulator of metabolism, the AMP-activated protein kinase (AMPK) is an established therapeutic target for metabolic diseases. Beyond the metabolic area, the number of medical fields that involve AMPK grows continuously, expanding the potential applications for AMPK modulators. Even though indirect AMPK activators are used in the clinics for their beneficial metabolic outcome, the few described direct agonists all failed to reach the market to date, which leaves options open for novel targeting methods. As AMPK is not actually a single molecule and has different roles depending on its isoform composition, the opportunity for isoform-specific targeting has notably come forward, but the currently available modulators fall short of expectations. In this review, we argue that with the amount of available structural and ligand data, computer-based drug design offers a number of opportunities to undertake novel and isoform-specific targeting of AMPK.

Acute activation of endothelial AMPK surprisingly inhibits endothelium‐dependent hyperpolarization‐like relaxations in rat mesenteric arteries

“…The present observations are in line with earlier suggestions that A769662 has a more pronounced effect in vascular smooth muscle in which AICAR seems to be ineffective compared to its action in other tissues (Rubin et al, 2005;Schneider et al, 2015). A769662 and AICAR bind to different sites of AMPK (the former is a β1-selective activator, while the active metabolite of the latter binds to the γ-subunit, resulting in exposure of the kinase domain in the α-subunit; Miglianico et al, 2015;Salt & Hardie, 2017); however, the absence of a different distribution of enzyme subunits in the present preparations with and without endothelium cannot explain the divergent actions of the two activators, although the anatomically smaller number of endothelial cells in the intima compared to the larger amount of vascular smooth muscle makes the interpretation difficult.…”

“…In order to examine EDH‐mediated relaxations, arterial rings were incubated for 40 min with N ω ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME ; 10 −4 M; non‐selective inhibitor of eNOS to prevent the generation of NO; Li et al, ) and indomethacin (10 −5 M; non‐selective inhibitor of COXs to prevent the generation of vasoactive prostanoids, in particular, prostacyclin; Félétou, Huang, & Vanhoutte, ; Li et al, ). The AMPK activators, AICAR (10 −4 M) and A769662 (10 −4 M; Miglianico, Nicolaes, & Neumann, ; Salt & Hardie, ), and different pharmacological agents (to identify the signalling pathways involved) were added into the organ chambers (in addition to l ‐NAME and indomethacin) for 40 min before exposing the arterial rings to phenylephrine (10 −7 to 3 × 10 −6 M; the concentrations of phenylephrine applied during different treatments are shown in Table S2) or U46619 (3 × 10 −8 to 10 −7 M); once the contractions had stabilized, the preparations were exposed to cumulatively increasing concentrations of the following relaxing agents: ACh (10 −9 to 10 −5 M; the maximal responses to the muscarinic agonist were comparable irrespective of the concentration of phenylephrine needed to produce matched pre‐contractions during different treatments; Figure S4A) or bradykinin (10 −11 to 10 −6 M), which are gold standards for evoking endothelium‐dependent relaxations in rodent and porcine arteries, respectively (Furchgott & Zawadzki, ; Nagao & Vanhoutte, ), or SKA‐31 (10 −5 M; the concentration, within the range of 10 −9 to 10 −5 M, which caused significant relaxation in the rings [data not shown]; opener of K Ca 3.1 and K Ca 2 channels with EC 50 values of 260 nM and 2.9 μM, respectively; Sankaranarayanan et al, ).…”

Adenosine Monophosphate (AMP)-Activated Protein Kinase: A New Target for Nutraceutical Compounds

“…Due to the major importance of AMPK in body energy homeostasis, this enzyme has drawn the attention of many researchers as a suitable candidate for the treatment of several metabolic diseases [7]. …”

Identification of Direct Activator of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by Structure-Based Virtual Screening and Molecular Docking Approach

“…The β subunit serves as a scaffold to bridge α and γ subunits that contains a glycogen binding domain (GBD) and a C-terminal domain [ 10 ]. The γ subunit is composed of a β subunit-binding region and two Bateman domains [ 11 ]. These seven subunits (α1, α2, β1, β2, γ1, γ2, and γ3) are encoded by separate genes, resulting in 12 different αβγ AMPK heterotrimers [ 12 ].…”