Investigating of interactions between statin-based cholesterol lowering drugs with p-glycoprotein membrane protein by molecular modeling

Abstract

In this study, the interaction of P-glycoprotein (P-gp) with lactone form of cholesterol lowering atorvastatin and linear peptides including ALLM (N-acetyl-leu-leu-met-al) and AFMRF (N-acetyl-phemet-arg-phe-al) were investigated by using molecular dynamics simulation. P-gp is a multidrug resistance protein which expels the toxic compounds out of the cell and in this way protects the cell from the harmful effect of these compounds. First, P-gp was integrated into 1,2-dimyristoyl-snglycero-3-phosphocholine (DMPC) lipid bilayer and solvated to investigate these interactions. Then Mg-ATP molecules, which supply the required energy for transportation, were docked into the nucleotide binding domains of the protein. After the preparation of the P-gp integrated lipid membrane system, simulations were run for each substrate. As a result, while no interaction was detected between the linear peptides and P-gp, lactone form of atorvastatin was found to have an interaction with the protein, leading to an asymmetrical closure of nucleotide binding domains. When the ability of P-gp to transport multiple substrates were taken into account, it could be said that single small peptides could not trigger the protein activity needed for transportation. The authors would like to acknowledged the grant from ITU-BAP.