Abstract
Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of energy metabolism and has been targeted for drug development of therapeutic intervention in Type II diabetes and related diseases. Recently, there has been renewed interest in the development of direct β1-selective AMPK activators to treat patients with diabetic nephropathy. To investigate the details of AMPK domain structure, sequence alignment and structural comparison were used to identify the key amino acids involved in the interaction with activators and the structure difference between β1 and β2 subunits. Additionally, a series of potential β1-selective AMPK activators were identified by virtual screening using molecular docking. The retrieved hits were filtered on the basis of Lipinski’s rule of five and drug-likeness. Finally, 12 novel compounds with diverse scaffolds were obtained as potential starting points for the design of direct β1-selective AMPK activators.
Highlights
Kidney disease associated with diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease worldwide and nearly one-third of patients with diabetes develop nephropathy [1]
Sequence alignment is an essential method for similarity/dissimilarity analysis of protein, DNA, or RNA sequences [24]
The crystallographic structures of AMPK for molecular docking studying were added to the hydrogen atoms and the charge was given to the Gasteiger-Huckel
Summary
Kidney disease associated with diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease worldwide and nearly one-third of patients with diabetes develop nephropathy [1]. BTohuisndimtopltihees athllaotsttehreicasliltoesatenrdicsshiotewceadnbbeteteurspedotetoncdyefsoigr nisothfoermsesletchtaivtecoanctaivinattohres βo1f sAuMbuPnKit.cTonhtiasiinminpglieths ethβa1t tshuebaulnloits.teric site can be used to design the selective activators of AMPK containing the β1 subunit. Analysis of Binding Mode of Activators for α1β1γ1 AMPK Isoform 2.4. Analysis of Binding Mode of Activators for α1β1γ1 AMPK Isoform TInht.eJ. Mstorl.uSccit.u20r1e7s, 1o8,f1r4e08trieved hits as activators of α1β1γ1 AMPK isoform are shown in Fofi1g1ure 5. Among these compounds, compounds F064-1335 and M5653-1884 possess higher docking scores, compounds M8006-4303 and F264-3019 have perfect drug-likeness model scores. The carbonyl oxygen of benzoxazolone ring formed a hydrogen bond with the side chain of Arg-83′. One carbonyl oxygen atom of 1,3-indandione formed hydrogen bond with the side chain of. Lys-31, another carbonyl oxygen atom formed a hydrogen bond with the main chain of Val-11. B-ring while the B-ring showed a stacked cation-π interaction with the side chain of Val-83′
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