Characterizing the binding interactions between P-glycoprotein and eight known cardiovascular transport substrates

Pharmacology Research & Perspectives
Justin C Jagodinsky, Ugur Akgun

Abstract

The multidrug efflux pump P-glycoprotein (Pgp) is upregulated in cardiomyocytes following chronic ischemia from infarction and hypoxia caused by sleep apnea. This report summarizes the molecular dynamic studies performed on eight cardiovascular drugs to determine their corresponding binding sites on mouse Pgp. Selected Pgp transport ligands include: Amiodarone, Bepridil, Diltiazem, Dipyridamole, Nicardipine, Nifedipine, Propranolol, and Quinidine. Extensive molecular dynamic equilibration simulations were performed to determine drug docking interactions. Distinct binding sites were not observed, but rather a binding belt was seen with multiple residues playing a role in each studied drug's stable docking. Three key drug-protein interactions were identified: hydrogen bonding, hydrophobic packing, and the formation of a "cage" of aromatic residues around the drug. After drug stabilization, water molecules were observed to leak into the binding belt and condense around the drug. Water influx into the binding domain of Pgp may play a role in catalytic transition and drug expulsion. The cytoplasmic recruitment theory was also tested, and the drugs were observed to interact with conserved loops of residues with a strong affinity. A f...Continue Reading

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Citations

May 18, 2016·Neurochemistry International·Nandhitha SubramanianMegan L O'Mara
Oct 28, 2016·Basic & Clinical Pharmacology & Toxicology·Junfang ZhaoXin Wang
Mar 21, 2020·Frontiers in Oncology·Kianna Robinson, Venkataswarup Tiriveedhi
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Feb 18, 2021·Physical Chemistry Chemical Physics : PCCP·Bo ZhangQi Wang
Mar 25, 2021·Chemical Reviews·Peter J F HendersonKarl A Hassan

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Methods Mentioned

BETA
glycosylation
X-ray

Software Mentioned

mdff
VMD package
VMD
VMD RMSD Trajectory
Linux
psfgen
NAMD
MolProbity
visual molecular dynamics program suite ( VMD )

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