Predicting Binding to P-Glycoprotein by Flexible Receptor Docking

Dolghih, Elena; Bryant, Clifford; Renslo, Adam R.; Jacobson, Matthew P.

doi:10.1371/journal.pcbi.1002083

Cited by 95 publications

(92 citation statements)

References 51 publications

(65 reference statements)

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“…We studied the active form of P-gp because of a need for conformational change to activate P-gp (28). The active P-gp was increased in GBM cells, acutely and chronically treated with temozolomide ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells

Munoz

Rodriguez-Cruz

Greco

et al. 2014

Molecular Cancer Therapeutics

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Glioblastoma multiforme (GBM) commonly resists the frontline chemotherapy treatment temozolomide. The multidrug resistance gene (MDR1) and its protein, P-glycoprotein (P-gp), are associated with chemoresistance. This study investigated the mechanisms underlying MDR1-mediated resistance by GBM to temozolomide. P-gp trafficking was studied by flow cytometry and Western blot analysis. MDR1 expression was analyzed by real-time PCR and reporter gene assays. AP-1 interaction with MDR1 was studied by chromatin immunoprecipitation assay. EGF production was analyzed by ELISA, EGFR signaling was determined by Western blot analysis, and in vivo response to erlotinib and/or temozolomide was studied in nude mice. During the early phase of temozolomide treatment, intracellular P-gp was trafficked to the cell membrane, followed by conformational change into active P-gp. At the later phase, gene transcription of MDR1 was induced by temozolomide-mediated production of EGF. EGF activated ERK1/2-JNK-AP-1 cofactors (c-jun and c-fos). An inhibitor of EGFR kinase (erlotinib) given to nude mice with GBM prevented temozolomideinduced resistance. The results identified an essential role for activated EGFR in the resistance of GBM to temozolomide. Temozolomide resistance occurred through a biphasic response; first, by a conformational change in P-gp into the active form and, second, by releasing EGF, which caused autocrine stimulation of GBM cells to induce MDR1. Pharmacologic inhibition of EGFR kinase blunted the ability of GBM cells to resist temozolomide. These findings may explain reports on the common occurrence of mutant EGFR (EGFRvIII) and EGFR expansion in the resistance of GBM cells. Mol Cancer Ther; 13(10); 2399-411. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells

Munoz

Rodriguez-Cruz

Greco

et al. 2014

Molecular Cancer Therapeutics

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“…Recent analyses had shown that docking studies performed by various approaches are reliable strategies to identify compounds that interact directly with ABCB1 [51][52][53]. From our previous studies, the docking scores obtained for a group of 54 substrates (including well-known substrates such as ivermectin and cyclosporine) had an average docking score of ≤ −12, like those we observed for enzastaurin in the 3G60 structure, while a group of 69 nonsubstrates had an average score of ~ −10 kcal/mol using MOE software and the same docking methodology [54,55].…”

Section: Discussionmentioning

confidence: 99%

Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status

Michaelis¹,

Rothweiler²,

Löschmann³

et al. 2016

European Journal of Cancer

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The Computational docking experiments detected a direct interaction of enzastaurin and ABCB1. These data suggest that enzastaurin directly interferes with ABCB1 function. Enzastaurin further inhibited ABCG2-mediated drug transport but by a different mechanism since it reduced ABCG2 ATPase activity. These findings are important for the further development of therapies combining enzastaurin with ABC transporter substrates.

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“…Flexible receptor docking was performed using a multistage induced fit docking protocol (IFD) as described in detail previously. 20 Briefly, in the first stage, the van der Waals radii of protein and ligand are scaled by a factor of 0.5 and ligands are docked into the receptor using the default GlideSP mode. Next, Prime is used to predict and optimize selected protein side chains.…”

Section: ■ Methodsmentioning

confidence: 99%

Predicting Efflux Ratios and Blood-Brain Barrier Penetration from Chemical Structure: Combining Passive Permeability with Active Efflux by P-Glycoprotein

Dolghih

Jacobson

2012

ACS Chem. Neurosci.

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In order to reach their pharmacologic targets, successful central nervous system (CNS) drug candidates have to cross a complex protective barrier separating brain from the blood. Being able to predict a priori which molecules can successfully penetrate this barrier could be of significant value in CNS drug discovery. Herein we report a new computational approach that combines two mechanism-based models, for passive permeation and for active efflux by P-glycoprotein, to provide insight into the multiparameter optimization problem of designing small molecules able to access the CNS. Our results indicate that this approach is capable of distinguishing compounds with high/low efflux ratios as well as CNS+/CNS− compounds and provides advantage over estimating P-glycoprotein efflux or passive permeability alone when trying to predict these emergent properties. We also demonstrate that this method could be useful for rank-ordering chemically similar compounds and that it can provide detailed mechanistic insight into the relationship between chemical structure and efflux ratios and/or CNS penetration, offering guidance as to how compounds could be modified to improve their access into the brain. KEYWORDS: P-glycoprotein, CNS drugs, blood brain barrier, BBB, efflux ratio prediction, structure-based ADME prediction O ne of the unique challenges of developing drugs for the central nervous system (CNS) is overcoming the bloodbrain barrier (BBB), a cellular and enzymatic barrier that tightly regulates passage of molecules from blood into the brain. Formed by the endothelium of the cerebral blood capillaries, it has several distinct features. Tight junctions between the endothelial cells prevent paracellular transport or diffusion of molecules in the space between the cells, which effectively limits molecular access to the brain to transcellular permeation.3 Another feature is highly expressed active efflux transporters that expel diffusing molecules back into the blood. Among these, P-glycoprotein (also referred to by its gene name MDR1 or ABCB1) is the most abundant and is known to efflux molecules of a wide variety of shapes and sizes with no one single pharmacophore. 4 A recently published structure of mouse P-glycoprotein, Figure 1, revealed a large hydrophobic cavity in the transmembrane region lined with various hydrophobic and flexible side-chains with no clearly defined subsites, offering an explanation for the broad substrate specificity. 5,6 Several in vitro methods have been developed to predict brain penetration of CNS drug candidates. The most widely used assays employ cell monolayers, such as the MDR-MDCK, that is, Madin-Darby canine kidney cells that have been modified to overexpress P-glycoprotein, which localizes on the apical cell surface. In such assays, transport rates of molecules are measured in both directions, basal-to-apical and apical-tobasal, across the single layer of cells. The ratio or difference of the two rates in opposite directions is used to identify P-gp substrates and to predict...

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Predicting Binding to P-Glycoprotein by Flexible Receptor Docking

Cited by 95 publications

References 51 publications

Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells

Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells

Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status

Predicting Efflux Ratios and Blood-Brain Barrier Penetration from Chemical Structure: Combining Passive Permeability with Active Efflux by P-Glycoprotein

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