Toward a Better Pharmacophore Description of P-Glycoprotein Modulators, Based on Macrocyclic Diterpenes from <i>Euphorbia</i> Species

Ferreira, Ricardo B.; Santos, Daniel J. V. A. dos; Ferreira, Maria‐José U.; Guedes, Rita C.

doi:10.1021/ci200145p

Cited by 57 publications

(55 citation statements)

References 34 publications

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“…In the particular case of verapamil, the increased nonbonded interactions established, which is also shown by the modulator tariquidar, classifies the molecule as a modulator. This is well in accordance with a previously developed pharmacophore [79], where the ability to establish a greater number of hydrophobic interactions within the pocket is one of the major features that allows a molecule to block competitively the substrate binding. These studies convincingly demonstrate that structure-based modeling in the field of ABC-transporter has become a valuable tool for a deeper understanding of the molecular features driving ligand–transporter interaction.…”

Section: Structure-based Modelssupporting

confidence: 89%

Prediction of drug–ABC-transporter interaction — Recent advances and future challenges

Montanari

Ecker

2015

Advanced Drug Delivery Reviews

183

112

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With the discovery of P-glycoprotein (P-gp), it became evident that ABC-transporters play a vital role in bioavailability and toxicity of drugs. They prevent intracellular accumulation of toxic compounds, which renders them a major defense mechanism against xenotoxic compounds. Their expression in cells of all major barriers (intestine, blood-brain barrier, blood-placenta barrier) as well as in metabolic organs (liver, kidney) also explains their influence on the ADMET properties of drugs and drug candidates. Thus, in silico models for the prediction of the probability of a compound to interact with P-gp or analogous transporters are of high value in the early phase of the drug discovery process. Within this review, we highlight recent developments in the area, with a special focus on the molecular basis of drug-transporter interaction. In addition, with the recent availability of X-ray structures of several ABC-transporters, also structure-based design methods have been applied and will be addressed.

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Section: Structure-based Modelssupporting

confidence: 89%

Prediction of drug–ABC-transporter interaction — Recent advances and future challenges

Montanari

Ecker

2015

Advanced Drug Delivery Reviews

183

112

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“…10 Our previous studies with jolkinol D derivatives on the ability of macrocyclic diterpenes to revert Pgp-mediated MDR corroborate this structural feature. 9 Therefore, in this work, using several aromatic acyl chlorides, six new analogues of epoxyboetirane A (1) were prepared (7)(8)(9)(10)(11)(12). Compounds 13 and 14 were also prepared aiming to evaluate the influence of the number of carbon atoms of the alkanoyl residues on the activity.…”

Section: Inhibition Of Rhodamine-123 Efflux Pgp-mediatedmentioning

confidence: 56%

“…7,8 Aiming to optimize macrocyclic diterpenes as MDR reversal agents, 9,10 herein we report the isolation of five lathyrane diterpenes http://dx.doi.org/10.1016/j.bmc.2014.09.041 0968-0896/Ó 2014 Elsevier Ltd. All rights reserved. (1)(2)(3)(4)(5), including two new compounds (1 and 2), from Euphorbia boetica.…”

Section: Introductionmentioning

confidence: 99%

“…(1)(2)(3)(4)(5), including two new compounds (1 and 2), from Euphorbia boetica. Furthermore, compound 1, isolated in large amounts, was hydrolyzed and the resulting parental polyalcohol (6) was subsequently acylated affording eight new derivatives (7)(8)(9)(10)(11)(12)(13)(14). Compounds 1-14 were evaluated for their ability as Pgp modulators, through the rhodamine-123 exclusion assay.…”

Section: Introductionmentioning

confidence: 99%

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Improving the MDR reversal activity of 6,17-epoxylathyrane diterpenes

Vieira

Duarte

Reis

et al. 2014

Bioorganic & Medicinal Chemistry

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“…Our pharmacophore model (AADDRRR) derived from nilotinib analogues was in accord with previously developed P-gp pharmacophore models (multiples of hydrogen bond acceptors, hydrogen bond donors, aromatic ring centers, or hydrophobes) derived from different structural classes. 33−35 This highlights the fact that the P-gp drug-binding cavity recognizes a set of appropriately spaced pharmacophoric features irrespective of the structure in which they are embedded, thus reinforcing the broad substrate/inhibitor specificity of P-gp. When this pharmacophore hypothesis was used as a query to map tariquidar and elacridar, we were able to match five (A5, D7, R13, R14, and R15) of the seven features onto tariquidar and six (A1, A5, D7, R14, and R15) of the seven features onto elacridar (data not shown).…”

Section: Discussionmentioning

confidence: 95%

Pharmacophore Modeling of Nilotinib as an Inhibitor of ATP-Binding Cassette Drug Transporters and BCR-ABL Kinase Using a Three-Dimensional Quantitative Structure–Activity Relationship Approach

et al. 2014

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Nilotinib (Tasigna) is a tyrosine kinase inhibitor approved by the FDA to treat chronic phase chronic myeloid leukemia patients. It is also a transport substrate of the ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which may have an effect on the pharmacokinetics and toxicity of this drug. The goal of this study was to identify pharmacophoric features of nilotinib in order to potentially develop specific inhibitors of BCR-ABL kinase with minimal interactions with ABC drug transporters. Three-dimensional pharmacophore modeling and quantitative structure–activity relationship (QSAR) studies were carried out on a series of nilotinib analogues to identify chemical features that contribute to inhibitory activity of nilotinib against BCR-ABL kinase activity, P-gp, and ABCG2. Twenty-five derivatives of nilotinib were synthesized and were then tested to measure their activity to inhibit BCR-ABL kinase and to inhibit the function of ABC drug transporters. A set of in vitro experiments including kinase activity and cell-based transport assays and photolabeling of P-gp and ABCG2 with a transport substrate, [125I]-iodoarylazido-prazosin (IAAP), were carried out in isolated membranes to evaluate the potency of the derivatives to inhibit the function of ABC drug transporters and BCR-ABL kinase. Sixteen, fourteen, and ten compounds were selected as QSAR data sets, respectively, to generate PHASE v3.1 pharmacophore models for BCR-ABL kinase, ABCG2, and P-gp inhibitors. The IC50 values of these derivatives against P-gp, ABCG2, or BCR-ABL kinase were used to generate pharmacophore features required for optimal interactions with these targets. A seven-point pharmacophore (AADDRRR) for BCR-ABL kinase inhibitory activity, a six-point pharmacophore (ADHRRR) for ABCG2 inhibitory activity, and a seven-point pharmacophore (AADDRRR) for P-gp inhibitory activity were generated. The derived models clearly demonstrate high predictive power for test sets of BCR-ABL, ABCG2, and P-gp inhibitors. In aggregate, these results should aid in the development of specific inhibitors of BCR-ABL kinase that exhibit no or minimal interaction with ABC drug transporters.

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Toward a Better Pharmacophore Description of P-Glycoprotein Modulators, Based on Macrocyclic Diterpenes from Euphorbia Species

Cited by 57 publications

References 34 publications

Prediction of drug–ABC-transporter interaction — Recent advances and future challenges

Prediction of drug–ABC-transporter interaction — Recent advances and future challenges

Improving the MDR reversal activity of 6,17-epoxylathyrane diterpenes

Pharmacophore Modeling of Nilotinib as an Inhibitor of ATP-Binding Cassette Drug Transporters and BCR-ABL Kinase Using a Three-Dimensional Quantitative Structure–Activity Relationship Approach

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