Lead Identification for Modulators of Multidrug Resistance based on <i>in silico</i> Screening with a Pharmacophoric Feature Model

Langer, Thierry; Eder, Monika; Hoffmann, Rémy D.; Chiba, Peter; Ecker, Gerhard F.

doi:10.1002/ardp.200300817

Cited by 63 publications

(34 citation statements)

References 28 publications

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“…To date, several P-gp models derived from both efflux and inhibition data have been reported (Ekins and Swaan, 2004;Chang and Swaan, 2005), but application of these models to identify novel P-gp substrates or inhibitors has not been explored. Recently, Langer et al (2004) described a P-gp pharmacophore that was subsequently utilized to screen molecular databases to select putative P-gp inhibitors. However, without in vitro validation of the predicted molecules, the impact of the work and the validity of the predictions remain to be seen.…”

Section: Discussionmentioning

confidence: 99%

“…In current drug discovery, the prospective application of pharmacophore models for database screening and the identification of P-gp substrates/inhibitors is limited (for a review, see Chang and Swaan, 2005) and not usually supported by experimental verification (Langer et al, 2004). Therefore, the objectives of the present study were to utilize and validate three unique P-gp pharmacophore models derived from substrate and inhibition data.…”

Section: Introductionmentioning

confidence: 99%

“…This is reflected in the existence of multiple models, which account for multiple binding sites and allosteric mechanisms of interaction. Thus, we have previously developed P-gp pharmacophore models from in vitro data for several cell systems using substrate transport data (Yates et al, 2003), as well as models with inhibition data (Ekins et al, 2002a,b).In current drug discovery, the prospective application of pharmacophore models for database screening and the identification of P-gp substrates/inhibitors is limited (for a review, see Chang and Swaan, 2005) and not usually supported by experimental verification (Langer et al, 2004). Therefore, the objectives of the present study were to utilize and validate three unique P-gp pharmacophore models derived from substrate and inhibition data.…”

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confidence: 99%

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Rapid Identification of P-glycoprotein Substrates and Inhibitors

Chang

Bahadduri²,

Polli³

et al. 2006

Drug Metab Dispos

135

105

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ABSTRACT:Identifying molecules that interact with P-glycoprotein (P-gp) is important for drug discovery but is also generally reliant on timeconsuming in vitro and in vivo studies. As an alternative approach, the current study applied pharmacophore models and database screening to rapidly retrieve molecules that bind as substrates or inhibitors for P-gp from commercial databases and then confirmed their affinity as inhibitors in vitro. Seven molecules (acitretin, cholecalciferol, misoprostol, nafcillin, repaglinide, salmeterol, and telmisartan) with no published details for P-gp affinity, one positive control inhibitor (miconazole), and two negative control molecules (phenelzine and zonisamide) were selected for testing. The MDCK-MDR1 in vitro cell model was used to confirm their inhibitory effect on [ 3 H]digoxin transport, and the ATPase assay was used as an additional in vitro tool to indicate P-gp activation. All seven test drugs were confirmed to have P-gp affinity. Additionally, our experimental results provided plausible explanations for the published pharmacokinetic profiles of the tested drugs and their classification according to the biopharmaceutics and drug disposition classification system. In this study, we showed the successful application of pharmacophore models to accurately predict P-gp binding, which holds promise to anticipate drug-drug interactions from screening drug databases and a priori prediction of novel P-gp inhibitors or substrates.Assessment of P-glycoprotein (P-gp, ABCB1) affinity in humans is a rate-limiting step in the identification of drug efficacy and safety. Apart from serving as a key factor in the natural detoxification mechanism in various human tissues, expression of P-gp also mediates efflux of xenobiotics. This generally results in reduced bioavailability as a result of increased hepatic, renal, and/or intestinal clearance of substrate drugs. Because of its frequent involvement in drug absorption, distribution, metabolism, and excretion, screening for in vivo and in vitro P-gp-mediated transport has become an essential component of the drug discovery process; this, in turn, may have led to the mounting costs of identifying clinical drug candidates. Attempts to coadminister P-gp modulators, inhibitors, or inducers to increase cellular availability by blocking the actions of P-gp have been met with limited success. As a result, there is a great need to identify whether a new chemical entity has affinity for P-gp and to understand the effects of P-gp on drug pharmacokinetics and pharmacodynamics. Thus, the rapid identification of P-gp substrates or inhibitors would be advantageous.Despite its overall significance, P-gp is poorly characterized at the atomic level, in large part because of the intrinsic difficulties involved in membrane protein crystallization. As an alternative, computational modeling of transporters has aided our understanding and has significantly increased our knowledge of transporter mechanisms and drug-transporter interactions. However, in the case of ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Rapid Identification of P-glycoprotein Substrates and Inhibitors

Chang

Bahadduri²,

Polli³

et al. 2006

Drug Metab Dispos

135

105

View full text Add to dashboard Cite

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“…The results obtained in this study are consistent with the recent findings by three dimensional quantitative structure activity relationship model studies. 20) Flavonoids seem to have the potential to overcome the multidrug resistance that results from the active efflux of anti-tumor drugs by P-gp. On the basis of this study, further studies are currently in progress to clarify the structural requirements for the inhibitory effects of a wide variety of flavonoids, including those which have large substituents as well as other polyphenols such as alkyl gallates.…”

Section: Discussionmentioning

confidence: 99%

Structure-Activity Relationships of the Inhibitory Effects of Flavonoids on P-Glycoprotein-Mediated Transport in KB-C2 Cells

Kitagawa

Nabekura

Takahashi

et al. 2005

Biological & Pharmaceutical Bulletin

111

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Overexpression of P-glycoprotein (P-gp), a plasma membrane transporter which extrudes chemotherapeutic agents out of cells, has been associated with the multidrug resistance of cancer cells. Compounds such as verapamil, dihydropyridine analogs, quinidine and cyclosporin A reversed this P-gp-mediated multidrug resistance (MDR) due to their inhibition of transporter activity. 1,2) In addition to these compounds, it has been revealed that flavonoids and other polyphenols modulate P-gp activity. [3][4][5][6] Although the structure-activity relationships of flavonoids on P-gp functions have been studied, 5,7,8) they are still not clear, especially concerning their effects in whole cells. Recently, we revealed that tea catechins inhibited P-gp function dependent on their chemical structure in multidrug-resistant human epidermal carcinoma cell line KB-C2 cells, 9) which overexpress P-gp. 10)Among the tea catechins, we found the maximum activity in the (Ϫ)epigallocatechin gallate whose chemical structure is shown in Fig. 1. We clarified that the presence of the galloyl moiety in the C ring, and the presence of the trihydric pyrogallol group as the B ring instead of the dihydric catechol group, markedly increased its activity on P-gp, although their effects on the partition coefficients between n-octanol and phosphate-buffered saline (PBS) were opposite to each other. 9)In this study, we examined the structure-activity relationships of seven flavonoids, naringenin (flavanone), baicalein (flavone), kaempferol, quercetin, myricetin, morin, and fisetin (flavonols) (Fig. 1), which do not have large substituents like the galloyl group, as well as two glycosides of quercetin, for their effects on P-gp-mediated drug extrusion in KB-C2 cells. We analyzed the effects from the standpoints of chemical structure, conformation and hydrophobicity. We studied the importance of the 2,3-double bond in the C ring, in relation to the stereoscopic structure of flavonoids. Furthermore, we studied the effects of hydrophobicity of the flavonoids on the inhibitory activity to P-gp function. For this study, we used fluorescent rhodamine-123 and daunorubicin as the P-gp substrates; these substrates have often been used for the study of various P-gp transport modulators including flavonoids.3,6,11) Although daunorubicin has also been revealed to be a substrate of multidrug resistance-associated protein 1 (MRP1), 12) since MRP1 is rarely found in KB-C2 cells, 13) its involvement in substrate efflux is negligible. We studied the effects of flavonoids, naringenin (flavanone), baicalein (flavone), kaempferol, quercetin, myricetin, morin, and fisetin (flavonols) as well as two glycosides of quercetin on P-glycoprotein (P-gp) function in multidrug-resistant P-gp overexpressing KB-C2 cells. Flavonoids such as kaempferol and quercetin increased the accumulation of rhodamine-123 dependent on their chemical structure. Analysis by flow cytometry indicated that the increase in substrate accumulation was due to the inhibition of substrate efflux. Naringenin, w...

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“…After applying an additional shape filter, 32 structurally diverse hits were retrieved. Nine out of these 32 compounds have already been described as P-gp inhibitors [86]. Thus, it is rather likely that the other compounds selected also bind to P-gp.…”

Section: Sar-and Qsar Studies On Inhibitors Of Abc Transportersmentioning

confidence: 99%