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

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 free energy change of astronomical value is required to recruit the drug from the cytoplasm to the binding belt within the transmembrane domain of Pgp.

SUBMITTER: Jagodinsky JC

PROVIDER: S-EPMC4324688 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Jagodinsky Justin C JC Akgun Ugur U

Pharmacology research & perspectives 20150301 2

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 simula ...[more]

PMID: 25729581

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Project description:BackgroundThe American Heart Association's (AHA) Life's Essential 8 (LE8) score is a helpful tool to quantify cardiovascular health (CVH) metrics. We sought to assess sex differences in relation to LE8 and its components along with association with mortality.MethodsThe National Health and Nutrition Examination Survey (NHANES) between 2009 and 2018 was utilized to evaluate the prevalence of health metrics included in LE8 among adult participants > age 18, stratified by sex. We categorized overall CVH, health factors, and health behaviors into 3 levels (low: <50, moderate: 50 -79, high: ≥80) following the AHA's algorithm. Health metrics were further subdivided into health behaviors (diet, physical activity, nicotine exposure, and sleep) and health factors (body mass index, non-high density lipoprotein cholesterol, blood glucose, and blood pressure). LE8 scores were also evaluated based on age, race/ethnicity, and socioeconomic status. Cox proportional hazard models were used to evaluate the association between the levels of CVH and risk of all-cause and cardiovascular mortality, with adjustment for age group and race.ResultsAmong 22,761 participants, 52 % were female. Overall CVH score was similar in both females and males (65.8 vs. 65.9). Females had higher health factors score (64.3 vs. 63.1, p < 0.001) and lower health behaviors score (67.2 vs 68.6, p < 0.001). Amongst individual metrics, blood pressure score was higher in females (73.2 vs. 67.7, p < 0.001) while males had higher physical activity score (70.6 vs. 54.9, p < 0.001). For individuals under 65 years of age, overall CVH and health factors scores were higher in females while in those age 65 or older, males had higher scores. The most prominent sex differences were noted in non-Hispanic Black females who had significantly lower CVH scores than Black males (62.6 vs. 74.7, respectively, p < 0.001. High LE8 scores vs. low LE8 scores demonstrated lower all-cause (HR 0.37 vs 0.35) and CV mortality (HR 0.35 vs. 0.36) in both males and females, respectively (p-interaction 0.21 and 0.28). High health behaviors scores also demonstrated a significant association with lower all-cause (0.34 vs. 0.24) and CV mortality (HR 0.47 vs. 0.26) in both males and females, respectively (p-interaction 0.20 and 0.11).ConclusionsWe demonstrate important sex differences in CVH metrics along with notable variations based on age and race/ethnicity. Furthermore, we highlight that CVH metrics including health factors and health behaviors are associated with mortality in both females and males. These findings underscore the importance of designing and implementing effective strategies for both sexes, aimed at targeting these specific factors.

Dataset Information

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

Publications

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

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