In silico screening with benzofurane- and benzopyrane-type MDR-modulators

Rebitzer, Sascha; Annibali, Danilo; Kopp, Stephan; Eder, Monika; Langer, Thierry; Chiba, Peter; Ecker, Gerhard F.; Noe, Christian R.

doi:10.1016/s0014-827x(03)00021-1

Cited by 13 publications

(3 citation statements)

References 18 publications

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“…Progress in understanding the role of the physicochemical properties relevant to important processes in membrane permeability (e.g., BBB) brings the rational design of novel effective drugs more within reach. In this contest, the use of computational in silico models can help in initial screening and effectively accelerate the drug development process but they still need to be supported by in vitro and in vivo studies to gather a number of crucial physicochemical measurements (e.g., those necessary to assess the contributions of passive and active transport) 120,121. Furthermore, at this stage, with respect to BBB, in silico models cannot be reliably used to predict brain distribution of a compound.…”

Section: In Silico Models: Advantages and Limitationsmentioning

confidence: 99%

In Vitro Blood–Brain Barrier Models: Current and Perspective Technologies

Naik

Cucullo

2012

Journal of Pharmaceutical Sciences

252

188

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Even in the 21st century, studies aimed at characterizing the pathological paradigms associated with the development and progression of central nervous system diseases are primarily performed in laboratory animals. However, limited translational significance, high cost, and labor to develop the appropriate model (e.g., transgenic or inbred strains) have favored parallel in vitro approaches. In vitro models are of particular interest for cerebrovascular studies of the blood–brain barrier (BBB), which plays a critical role in maintaining the brain homeostasis and neuronal functions. Because the BBB dynamically responds to many events associated with rheological and systemic impairments (e.g., hypoperfusion), including the exposure of potentially harmful xenobiotics, the development of more sophisticated artificial systems capable of replicating the vascular properties of the brain microcapillaries are becoming a major focus in basic, translational, and pharmaceutical research. In vitro BBB models are valuable and easy to use supporting tools that can precede and complement animal and human studies. In this article, we provide a detailed review and analysis of currently available in vitro BBB models ranging from static culture systems to the most advanced flow-based and three-dimensional coculture apparatus. We also discuss recent and perspective developments in this ever expanding research field.

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Section: In Silico Models: Advantages and Limitationsmentioning

confidence: 99%

In Vitro Blood–Brain Barrier Models: Current and Perspective Technologies

Naik

Cucullo

2012

Journal of Pharmaceutical Sciences

252

188

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“…The first such report appeared in 2003, where Rebitzer and colleagues used a propafenone derivative MDR modeluator-based pharmacophore model to screen Derwent World Drug Index. Among the returned 28 hits, 9 were previously described MDR-modulators [95]. A more detailed discussion of the P-gp pharmacophore-based database screening study were later published [96].…”

Section: P-gpmentioning

confidence: 99%

Pharmacophore-based discovery of ligands for drug transporters

Chang

Ekins

Bahadduri

et al. 2006

Advanced Drug Delivery Reviews

100

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The ability to identify ligands for drug transporters is an important step in drug discovery and development. It can both improve accurate profiling of lead pharmacokinetic properties and assist in the discovery of new chemical entities targeting transporters. In silico approaches, especially pharmacophore-based database screening methods have great potential in improving the throughput of current transporter ligand identification assays, leading to a higher hit rate by focusing in vitro testing to the most promising hits. In this review, the potential of different in silico methods in transporter ligand identification studies are compared and summarized with an emphasis on pharmacophore modeling. Various implementations of pharmacophore model generation, database compilation and flexible screening algorithms are also introduced. Recent successful utilization of database searching with pharmacophores to identify novel ligands for the pharmaceutically significant transporters hPepT1, P-gp, BCRP, MRP1 and DAT are reviewed and the challenges encountered with current approaches are discussed.

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“…Several ABCB1 pharmacophores have been used in screening databases. Rebizter and coworkers used a propafenone based pharmacophore model to screen the Derwent World Drug Index (119). This identified 19 new potential ABCB1 substrates but the study did not report subsequent experimental verification (120).…”

Section: What Is Pharmacophore Modeling?mentioning

confidence: 99%

Generating Inhibitors of P-Glycoprotein: Where to, Now?

Crowley

McDevitt

Callaghan

2009

Methods in Molecular Biology

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The prominent role for the drug efflux pump ABCB1 (P-glycoprotein) in mediating resistance to chemotherapy was first suggested in 1976 and sparked an incredible drive to restore the efficacy of anticancer drugs. Achieving this goal seemed inevitable in 1982 when a series of calcium channel blockers were demonstrated to restore the efficacy of chemotherapy agents. A large number of other compounds have since been demonstrated to restore chemotherapeutic sensitivity in cancer cells or tissues. Where do we stand almost three decades since the first reports of ABCB1 inhibition? Unfortunately, in the aftermath of extensive fundamental and clinical research efforts the situation remains gloomy. Only a small handful of compounds have reached late stage clinical trials and none are in routine clinical usage to circumvent chemoresistance. Why has the translation process been so ineffective? One factor is the multifactorial nature of drug resistance inherent to cancer tissues; ABCB1 is not the sole factor. However, expression of ABCB1 remains a significant negative prognostic indicator and is closely associated with poor response to chemotherapy in many cancer types. The main difficulties with restoration of sensitivity to chemotherapy reside with poor properties of the ABCB1 inhibitors: (1) low selectivity to ABCB1, (2) poor potency to inhibit ABCB1, (3) inherent toxicity and/or (4) adverse pharmacokinetic interactions with anticancer drugs. Despite these difficulties, there is a clear requirement for effective inhibitors and to date the strategies for generating such compounds have involved serendipity or simple chemical syntheses. This chapter outlines more sophisticated approaches making use of bioinformatics, combinatorial chemistry and structure informed drug design. Generating a new arsenal of potent and selective ABCB1 inhibitors offers the promise of restoring the efficacy of a key weapon in cancer treatment--chemotherapy.

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In silico screening with benzofurane- and benzopyrane-type MDR-modulators

Cited by 13 publications

References 18 publications

In Vitro Blood–Brain Barrier Models: Current and Perspective Technologies

In Vitro Blood–Brain Barrier Models: Current and Perspective Technologies

Pharmacophore-based discovery of ligands for drug transporters

Generating Inhibitors of P-Glycoprotein: Where to, Now?

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