Pharmacological Targeting of AMP-Activated Protein Kinase and Opportunities for Computer-Aided Drug Design.
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.
Department of Molecular Genetics, and ‡Department of Biochemistry, CARIM School for Cardiovascular Diseases, Maastricht University , NL-6200 MD, Maastricht, The Netherlands.
Marie
M
Miglianico
Department of Molecular Genetics, and ‡Department of Biochemistry, CARIM School for Cardiovascular Diseases, Maastricht University , NL-6200 MD, Maastricht, The Netherlands.
Gerry A F
GA
Nicolaes
Department of Molecular Genetics, and ‡Department of Biochemistry, CARIM School for Cardiovascular Diseases, Maastricht University , NL-6200 MD, Maastricht, The Netherlands.
Dietbert
D
Neumann
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D017076:Computer-Aided Design; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D008024:Ligands; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D008024:Ligands; D047428:Protein Kinase Inhibitors; D055372:AMP-Activated Protein Kinases