Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1

Tajima, Yasuhiro; Nakagawa, Hiroshi; Tamura, Ai; Kadioglu, Onat; Satake, Kazuhiro; Mitani, Yuji; Murase, Hayato; Regasini, Luís Octávio; Bolzani, Vanderlan da Silva; Ishikawa, Toshihisa; Fricker, Gert; Efferth, Thomas

doi:10.1016/j.phymed.2013.08.024

Cited by 33 publications

(16 citation statements)

References 30 publications

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“…This approach was also followed by Tajima et al in order to identify the P‐gp binding capability of a novel guanidine alkaloid, Nitensidine A. Binding of Nitensidine A analogs and verapamil were shown to dock at the same binding pocket with similar binding energies, number, and type of residues involved . Finally, similar conclusions on the location of the DBS and residues involved in drug binding were reported recently .…”

Section: Structure‐based Drug Discovery In Mdrmentioning

confidence: 54%

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Ferreira

Santos

2014

WIREs Comput Mol Sci

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One of the greatest threats to cancer treatment is the development, by some tumors, of resistance to the pharmacological action of several structurally unrelated cytotoxic agents-multidrug resistance (MDR). As P-glycoprotein (P-gp) is one of the most studied ATP-dependent efflux pumps that are frequently involved in drug efflux from cancer cells, the development of MDR modulators with the ability to inhibit P-gp efflux is considered a promising approach for overcoming MDR. However, the development of P-gp modulators have been hampered due to the absence of knowledge on the intrinsic molecular aspects by which efflux occurs, namely the specific steps that correlates drug recognition, ATP binding and efflux-related conformational changes. Experimental evidences for these processes are also difficult to obtain and only provide small pieces of information that need to be assembled for better comprehension of a wider and complex process that is drug efflux. A promising alternative relies on cutting-edge computational techniques to provide new insights on key aspects that are determinant to understand how P-gp efflux can be effectively reversed. With the contribution of ligand-based or structure-based computational methods, P-gp drug efflux is slowly becoming a dynamic and reactive process rather than a simple response to drug binding, with the complex architecture of ABC transporters playing a determinant role not only in drug recognition but in the coordination of ATP-driven conformational changes that ultimately drives drug efflux. The major enlightenments that computational studies provided toward a better comprehension of MDR and P-gp efflux phenomena are hereby described.The demographic effect of this pathology on the general population, especially in the industrialized countries, is becoming severely affected by a rapid increase in the number of new cancers (Figure 1). It is estimated that by 2030 the number of new cases (excluding nonmelanoma skin cancer) will grow 32.8% (more than 21 million), with an estimated increase of 34.6% (1.3 million) in the total number of deaths. 2,3 Thus, new and improved chemotherapy regimens are needed to counterweight such predictions. However, cancer therapy evolution is directly related to a greater knowledge on the basic molecular mechanisms Volume 5, January/February 2015 Although the above structures contributed to a better comprehension of the ABC exporters' topology, a Volume 5, January/February 2015

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Section: Structure‐based Drug Discovery In Mdrmentioning

confidence: 54%

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Ferreira

Santos

2014

WIREs Comput Mol Sci

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“…They were able to show that derivatives could be designed that inhibited P-gp and also led to an improved in vitro efficacy in a sensitized drug-resistant (to doxorubicin) cell line [27]. Other studies have used docking to explore the binding of potential novel inhibitors such as 6-(methylsulfinyl)hexyl isothiocyanate [28] and guanidine alkaloid [29]. They found in each case that these drugs bind in similar locations to known P-gp inhibitors such as QZ59-RRR [28] and verapamil [29].…”

Section: Modelling Studiesmentioning

confidence: 99%

“…Other studies have used docking to explore the binding of potential novel inhibitors such as 6-(methylsulfinyl)hexyl isothiocyanate [28] and guanidine alkaloid [29]. They found in each case that these drugs bind in similar locations to known P-gp inhibitors such as QZ59-RRR [28] and verapamil [29]. Klepsch et al [30] explored the binding mode of propafenone derivatives in homology models derived from the Sav1866 and mouse crystal structures to capture the differences between the conformational states [30].…”

Section: Modelling Studiesmentioning

confidence: 99%

Homology modelling of human P-glycoprotein

Domicevica

Biggin

2015

Biochemical Society Transactions

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P-glycoprotein (P-gp) is an ATP-binding cassette transporter that exports a huge range of compounds out of cells and is thus one of the key proteins in conferring multi-drug resistance in cancer. Understanding how it achieves such a broad specificity and the series of conformational changes that allow export to occur form major, on-going, research objectives around the world. Much of our knowledge to date has been derived from mutagenesis and assay data. However, in recent years, there has also been great progress in structural biology and although the structure of human P-gp has not yet been solved, there are now a handful of related structures on which homology models can be built to aid in the interpretation of the vast amount of experimental data that currently exists. Many models for P-gp have been built with this aim, but the situation is complicated by the apparent flexibility of the system and by the fact that although many potential templates exist, there is large variation in the conformational state in which they have been crystallized. In this review, we summarize how homology modelling has been used in the past, how models are typically selected and finally illustrate how MD simulations can be used as a means to give more confidence about models that have been generated via this approach.

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“…The previously generated homology model of human P-gp (Tajima et al, 2014) was used for molecular docking studies with AutoDock 4 (Morris et al, 2009) on the drug-binding pocket. The residues at the drug-binding pocket were His61, Gly64, Leu65, Met69, Ser222, Leu304, Ile306,Tyr307, Phe336, Leu339, Ile340, Ala342, Phe343, Gln725, Phe728, Phe732, Leu762, Thr837, Ile868, Gly872, Phe942, Thr945, Tyr953, Leu975, Phe978, Ser979, Val982, Gly984, Ala985, Met986, Gly989, Gln990, and Ser993 (Aller et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

Mode of Action Analyses of Neferine, a Bisbenzylisoquinoline Alkaloid of Lotus (Nelumbo nucifera) against Multidrug-Resistant Tumor Cells

Kadioglu¹,

Law

Mok

et al. 2017

Front. Pharmacol.

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Neferine, a bisbenzylisoquinoline alkaloid isolated from the green seed embryos of Lotus (Nelumbo nucifera Gaertn), has been previously shown to have various anti-cancer effects. In the present study, we evaluated the effect of neferine in terms of P-glycoprotein (P-gp) inhibition via in vitro cytotoxicity assays, R123 uptake assays in drug-resistant cancer cells, in silico molecular docking analysis on human P-gp and in silico absorption, distribution, metabolism, and excretion (ADME), quantitative structure activity relationships (QSAR) and toxicity analyses. Lipinski rule of five were mainly considered for the ADME evaluation and the preset descriptors including number of hydrogen bond donor, acceptor, hERG IC50, logp, logD were considered for the QSAR analyses. Neferine revealed higher toxicity toward paclitaxel- and doxorubicin-resistant breast, lung or colon cancer cells, implying collateral sensitivity of these cells toward neferine. Increased R123 uptake was observed in a comparable manner to the control P-gp inhibitor, verapamil. Molecular docking analyses revealed that neferine still interacts with P-gp, even if R123 was pre-bound. Bioinformatical ADME and toxicity analyses revealed that neferine possesses the druggability parameters with no predicted toxicity. In conclusion, neferine may allocate the P-gp drug-binding pocket and prevent R123 binding in agreement with P-gp inhibition experiments, where neferine increased R123 uptake.

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Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1

Cited by 33 publications

References 30 publications

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Homology modelling of human P-glycoprotein

Mode of Action Analyses of Neferine, a Bisbenzylisoquinoline Alkaloid of Lotus (Nelumbo nucifera) against Multidrug-Resistant Tumor Cells

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