1. Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 2. Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 3. Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
P-glycoprotein (p-gp) is an atp-binding cassette (abc) transporter which belongs to multidrug resistance pump super family. these membrane proteins extrude molecules such as anticancer drugs to the extracellular matrix in tumor cells. prevention of accumulation of anticancer drugs leads to failure of cancer chemotherapy . several drug binding domains (dbd) have been distinguished for p-gp structure. it has been reported that van der waals interactions are more favorable for ligand binding than electrostatic contribution. moreover, it has been reported that binding of atp to the nucleotide-binding domains (nbd) is the driving force for this function.
Molecular dynamics simulation was used to evaluate a new 1, 4 dyhdropyridine derivative as an inhibitor of p-gp in the presence of a lipids bilayer. simulations were performed using the package gromacs 4.5.5 which installed on linux cluster in national high-performance computing center - isfahan university of technology. 3g60 crystallographic structure was taken from protein data bank ( pdb) site. the dppc128.pdb file was obtained from peter tieleman’s website and the 128 dppc bilayer replicated by 512 lipid to obtain a bigger bilayer that was considered to be suitable for membrane proteins. topology and coordinate files for new ligand obtained from prodrg. the inflategro method was used for packing lipids around the embedded protein. analysese studeis such as rmsd, rmsf, short-range electrostatic and vander waals interactions energy, distance between two nbds and also hydrogen bonding during in the simulation were performed.
We suggest that the inhibitor contacts with p-gp via several dbds so that the substrate cavities are occupied and conformational changes occur but this does not lead to extract inhibitor from cell. it is possible that the formation of special shapes of aromatic residues e.g. phenylalanine, around the inhibitor via conformational changes cause a decrease of atpase activity by the nbd
The conformational changes of p-gp by substrate will be further rather than inhibitor. decrease distance between two nbd will not continue when inhibitor places in dbd.
Drug binding domains (dbd), nucleotide-binding domains (nbd)