Computer-aided prediction and molecular mechanism investigation of active components in compound Kushen injection inhibiting p21-activated kinase 1
Targeting p21-activated kinase 1(PAK1)is a novel strategy for pancreatic cancer treatment.Compound Kushen injection contains many anti-pancreatic cancer components,but the specific targets are unknown.In this study,14α-hydroxymatrine,an active component of Kushen injection,was found to possess high binding free energy with the allosteric site of PAK1 by molecular docking based virtual screening.Molecular dynamics simulations suggested that 14α-hydroxymatrine caused the α1 and α2 helices of the allosteric site of PAK1 to extend outward to form a deep allosteric regulatory pocket.Meanwhile,14α-hydroxymatrine induced the β-folding region at the adenosine triphosphate(ATP)-binding pocket of PAK1 to close inward,resulting in the ATP-binding pocket in a"semi-closed"state which caused the inactivation of PAK1.After removal of 14α-hydroxymatrine,PAK1 showed a tendency to change from the inactive conformation to the active conformation.We supposed that 14α-hydroxymatrine of compound Kushen injection might be a reversible allosteric inhibitor of PAK1.This study used modern technologies and methods to study the active components of traditional Chinese medicine,which laid a foundation for the development and utilization of natural products and the search for new treatments for pancreatic cancer.
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