Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
Volume 244, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijbiomac.2023.125328
Keywords
FATP2; Molecular dynamics simulation; Drug discovery
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Diabetes is a major public health problem with end organ complications. This study aimed to identify potential inhibitors of FATP2 as a treatment for diabetes. By constructing a homology model and conducting virtual screening, 23 hits were selected from a diverse compound library. Two compounds showed high affinity inhibition of FATP2 and were further characterized. This study demonstrates the feasibility of using homology modeling and in silico screening to identify potential inhibitors of FATP2 for diabetes treatment.
Diabetes is a major public health problem due to morbidity and mortality associated with end organ complications. Uptake of fatty acids by Fatty Acid Transport Protein-2 (FATP2) contributes to hyperglycemia, diabetic kidney and liver disease pathogenesis. Because FATP2 structure is unknown, a homology model was constructed, validated by AlphaFold2 prediction and site-directed mutagenesis, and then used to conduct a virtual drug discovery screen. In silico similarity searches to two low-micromolar IC50 FATP2 inhibitors, followed by docking and pharmacokinetics predictions, narrowed a diverse 800,000 compound library to 23 hits. These candidates were further evaluated for inhibition of FATP2-dependent fatty acid uptake and apoptosis in cells. Two compounds demonstrated nanomolar IC50, and were further characterized by molecular dynamic simulations. The results highlight the feasibility of combining a homology model with in silico and in vitro screening, to economically identify high affinity inhibitors of FATP2, as potential treatment for diabetes and its complications.
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