Molecular docking studies and in vitro screening of new dihydropyridine derivatives as human MRP1 inhibitors

Sirisha, Kalam; Shekhar, Maddela Chandra; Kulandaivelu, Umasankar; Porika, Mahendar; Abbagani, Sadanandam; Garlapati, Achaiah; Reddy, V. M.

doi:10.1016/j.bmc.2011.03.051

Cited by 26 publications

(25 citation statements)

References 26 publications

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“…Dihydropyridines Certain synthetic dihydropyridine derivatives had modulating effects on the MRP1 ATPase as determined in membranes derived from MRP1‐transfected Sf 9 cells . Derivative IA 1 (1‐30 µM; Figure ) stimulated NEM‐SG‐activated (10 mM) MRP1 ATPase, while compound IIA 5 (1‐100 µM; Figure ) nearly quadrupled NEM‐SG‐stimulated ATPase activity.…”

Section: Atpase Activationmentioning

confidence: 99%

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

Wiese

Stefan

2019

Medicinal Research Reviews

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Several mechanisms of pharmacokinetic, metabolic, and regulatory nature have been elucidated to take part or act in concert in the phenomenon of multidrug resistance (MDR). MDR is characterized by cross‐resistance of cells against chemotherapeutic agents, which are used for treatment of e.g., cancer, bacterial infections, or human immunodeficiency virus (HIV) infections. One group of proteins that combines all three stated aspects—the metabolism and distribution of drugs as well as their own regulation—is adenosine triphosphate‐binding cassette (ABC) transporters. These efflux pumps use the energy of adenosine triphosphate hydrolysis for drug translocation from the membrane and the cytosol to the extracellular space, often with cotransport of a cosubstrate. Multidrug resistance‐associated protein 1 (MRP1, ABCC1) had been discovered as one major key player in cancer‐related MDR. The xenobiotic substrates include anthracyclines, vinca alkaloids, podophyllotoxins, as well as glutathione (GSH)‐adducts of certain cytostatics. Contrary to other transport proteins involved in cancer‐related MDR the activity of MRP1 is related to the GSH content of cells. A modern strategy to overcome MRP1‐associated MDR is besides its inhibition the activation of GSH efflux, enforcing cell death due to cellular stress. In addition, it has recently been found that MRP1 contributes to the β‐amyloid protein clearance in Alzheimer's disease (AD). Collectively, transport activation of MRP1 is of therapeutic value, and furthermore helps to elucidate the transport protein function and the mechanisms behind it. This review is meant to summarize the known concepts of MRP1 activation, which might contribute to a further understanding of MRP1 in particular and ABC transporters in general.

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Section: Atpase Activationmentioning

confidence: 99%

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

Wiese

Stefan

2019

Medicinal Research Reviews

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“…26 A homology model based on the nucleotide binding site of MDR-1 by Reddy suggested a preferred inhibitory conformation wherein both 4-heteroaryl and C3 and C-5 aryl amides adopted a roughly endo relationship, 27 which is analogous to the pharmacophore model suggested by Eckert. Based on consideration of the conformational dynamics of IDHPs, and available pharmacophore and homology modelling studies to date, we conclude that for optimal MDR-1 binding IDHPs likely adopt a conformation in which the branched aryl group is preferentially over the DHP moiety, or O- endo for 1k , as illustrated in Figure 1.…”

Section: Solution Spectra and Nuclear Overhausermentioning

confidence: 93%

4-Isoxazolyl-1,4-dihydropyridines exhibit binding at the multidrug-resistance transporter

Hulubei

Meikrantz

Quincy

et al. 2012

Bioorganic & Medicinal Chemistry

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“…27–29 The sequence alignment was generated using Clustal W, 30 the alignment of and the subsequent threading indicated high sequence homology to the human sequence with a sequence identify of 82.34%. To visualize the hypothetical interactions between 3c and MDR-1 molecular modeling was conducted.…”

Section: Homology Modelingmentioning

confidence: 99%

Fluorescent probes of the isoxazole–dihydropyridine scaffold: MDR-1 binding and homology model

Ulatowski

George

Hayes

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Isoxazole-1,4-Dihydropyridines (IDHPs) were tethered to Fluorescent moieties using double activation via a lanthanide assisted Weibreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis.

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Molecular docking studies and in vitro screening of new dihydropyridine derivatives as human MRP1 inhibitors

Cited by 26 publications

References 26 publications

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

4-Isoxazolyl-1,4-dihydropyridines exhibit binding at the multidrug-resistance transporter

Fluorescent probes of the isoxazole–dihydropyridine scaffold: MDR-1 binding and homology model

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