A Computational Ensemble Pharmacophore Model for Identifying Substrates of P-Glycoprotein

Penzotti, Julie E.; Lamb, Michelle L.; Evensen, Erik; Grootenhuis, Peter D. J.

doi:10.1021/jm0255062

Cited by 176 publications

(219 citation statements)

References 17 publications

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“…While relative lipophilicity, the presence of a basic nitrogen atom and molecular refractivity have been suggested to be important factors for efficient interaction of an MDR reversing agent with Pglycoprotein [154,155], the structural determinants or pharmacophore of chemically and pharmacologically diverse MDR modulators remain largely unknown. However, several reports have further defined important features of P-glycoprotein pharmacophore [156][157][158][159][160][161][162][163][164][165][166]. Recent structure-activity relationship studies ot P-glycoprotein substrates and modifiers indicate that if two substrates are applied simultaneously to P-glycoprotein, the compound with the higher potential to form hydrogen bonds generally acts as an inhibitor [159].…”

Section: Specific Inhibitorsmentioning

confidence: 99%

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Safa

2004

CMCACA

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A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance (MDR) is overexpression of the MDR1 product P-glycoprotein, known to bind to and transport a wide variety of agents. This review concentrates on the progress made toward understanding the role of this protein in MDR, identifying and characterizing the drug binding sites of P-glycoprotein, and modulating MDR by P-glycoprotein-specific inhibitors. Since our initial discovery that Pglycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein-specific photoaffinity analogs have been developed and used to identify the particular domains of Pglycoprotein capable of interacting with these analogs and other P-glycoprotein substrates. Furthermore, significant advances have been made in delineating the drug binding sites of this protein by studying mutant P-glycoprotein. Photoaffinity labeling experiments and the use of sitedirected antibodies to several domains of this protein have allowed the localization of the general binding domains of some of the cytotoxic agents and MDR modulators on P-glycoprotein. Moreover, site-directed mutagenesis studies have identified the amino acids critical for the binding of some of these agents to P-glycoprotein. Furthermore, equilibrium binding assays using plasma membranes from MDR cells and radioactive drugs have aided our understanding of the modes of drug interactions with P-glycoprotein. Based on the available data, a topological model of Pglycoprotein and the approximate locations of its drug binding sites, as well as a proposed classification of multiple drug binding sites of this protein, is presented in this review.

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Section: Specific Inhibitorsmentioning

confidence: 99%

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Safa

2004

CMCACA

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“…Pgp is a 170kDa full ABC transporter with extensive N-linked glycosylation that effluxes a wide range of hydrophobic drugs 6,7 . Pgp function is intricately linked with membrane cholesterol content, though the details of the association are controversial 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Contribution of the ATP Binding Cassette Transporter, P-glycoprotein, to in Vivo Cholesterol Homeostasis

et al. 2013

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P-glycoprotein (Pgp, encoded by ABCB1, commonly known as MDR1), an ATP-dependent transporter with a broad range of hydrophobic drug substrates, has been associated with the in vitro intracellular transport of cholesterol; however, these findings have not been confirmed in vivo. In this manuscript we tested the contributions of Pgp to in vivo cholesterol homeostasis by comparing the cholesterol phenotype of wild type mice with mice lacking both murine isoforms of Pgp (Abcb1a −/− /1b −/− ) by measuring cholesterol absorption, circulating cholesterol, and lipoprotein cholesterol profiles. The mice were fed diets containing normal or high levels of dietary fat (25% vs. 45% kcal from fat) and cholesterol (0.02% vs. 0.20% w/w) for 8 weeks to challenge their capacity to maintain homeostasis.There were no significant differences in cholesterol absorption, circulating cholesterol levels, and lipoprotein profiles between Pgp knockout and wild type mice fed matching diets. Compensatory shifts were observed in the activation of two key transcription factors involved in maintaining cholesterol balance, the Liver X Receptor and SREBP-2, which may have maintained the wild type phenotype in the knockout mice. Deletion of Pgp affected the molar composition of gallbladder bile when the mice were fed diets containing high levels of dietary fat, cholesterol, or both. The mole fraction of bile salts was reduced in the gallbladder bile of Pgp knockout mice while the mole fraction of cholesterol was increased.In this paper, we provide evidence that Pgp knockout mice maintain cholesterol homeostasis, even when challenged with high cholesterol diets. We suggest that the specific shifts in cholesterol regulatory networks identified in the jejunum and liver of the knockout mice may have compensated for the lack of Pgp. Our finding that Pgp knockout mice were unable to maintain

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“…QSAR and pharmacophore modeling were applied to study the common features of p-gp substrate, the interactions between substrate and P-gp [156][157][158][159][160][161]. On the basis of the obtained results, we can give some explanations to the broad structural variety of the P-gp substrates and inhibitors and give predicted models for discrimination between substrate and non-substrate, but at present the accuracy of those models is too limited to be applied in virtual screening.…”

Section: In Silico Prediction Of Adme Propertiesmentioning

confidence: 99%

Recent Development and Application of Virtual Screening in Drug Discovery: An Overview

Hou¹,

Xu²

2012

Frontiers in Medicinal Chemistry - (Volume 3)

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Virtual screening, especially the structure-based virtual screening, has emerged as a reliable, cost-effective and time-saving technique for the discovery of lead compounds. Here, the basic ideas and computational tools for virtual screening have been briefly introduced, and emphasis is placed on aspects of recent development of docking-based virtual screening, scoring functions in molecular docking and ADME/Tox-based virtual screening in the past three years (2000 to 2003). Moreover, successful examples are provided to further demonstrate the effectiveness of virtual screening in drug discovery.

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A Computational Ensemble Pharmacophore Model for Identifying Substrates of P-Glycoprotein

Cited by 176 publications

References 17 publications

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Evaluation of the Contribution of the ATP Binding Cassette Transporter, P-glycoprotein, to in Vivo Cholesterol Homeostasis

Recent Development and Application of Virtual Screening in Drug Discovery: An Overview

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