Prediction of brain:blood unbound concentration ratios in CNS drug discovery employing  in silico  and  in vitro  model systems

Liu, Houfu; Dong, Kelly; Zhang, Wandong; Summerfield, Scott; Terstappen, Georg C.

doi:10.1016/j.drudis.2018.03.002

Cited by 58 publications

(56 citation statements)

References 108 publications

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“…The QikProp software allowed further predictions on pharmacokinetic properties of 4 and 5 , based on similarities with those of the 95% of a dataset of known drugs and drug‐like compounds, e.g. predicted blockade of hERG K + channels, predicted Caco‐2 monolayer permeability, and predicted MDCK monolayer permeability . These preliminary predictions (data not shown) indicated that, at therapeutic concentrations, 4 might be expected to cross to the blood–brain barrier via passive diffusion.…”

Section: Resultsmentioning

confidence: 99%

Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico

Arroo

Sarı

Barut

et al. 2020

Phytochemical Analysis

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Introduction Tyrosinase is a multifunctional copper‐containing oxidase enzyme that catalyses the first steps in the formation of melanin pigments. Identification of tyrosinase inhibitors is of value for applications in cosmetics, medicine and agriculture. Objective To develop an analytical method that allows identification of drug‐like natural products that can be further developed as tyrosinase inhibitors. Results of in vitro and in silico studies will be compared in order to gain a deeper insight into the mechanism of action of enzyme inhibition. Method Using an in vitro assay we tested tyrosinase inhibitor effects of five structurally related flavones, i.e. luteolin (1), eupafolin (2), genkwanin (3), nobiletin (4), and chrysosplenetin (5). The strongest inhibitors were further investigated in silico, using enzyme docking simulations. Results All compounds tested showed modest tyrosinase inhibitory effect compared to the positive control, kojic acid. The polymethoxy flavones 4 and 5 exhibited the strongest tyrosinase inhibitory effect with the half maximal inhibitory concentration (IC50) values of 131.92 ± 1.75 μM and 99.87 ± 2.38 μM respectively. According to kinetic analysis 2, 4 and 5 were competitive inhibitors, whereas 1 and 3 were non‐competitive inhibitors of tyrosinase. Docking studies indicated that methoxy groups on 4 and 5 caused steric hindrance which prevented alternative binding modes in the tyrosinase; the methoxy groups on the B‐ring of these flavones faced the catalytic site in the enzyme. Conclusions The docking simulations nicely complemented the in vitro kinetic studies, opening the way for the development of predictive models for use in drug design.

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Section: Resultsmentioning

confidence: 99%

Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico

Arroo

Sarı

Barut

et al. 2020

Phytochemical Analysis

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“…This application is beneficial in delivering large molecules and nanoparticles, but it is limited to a small area of the brain. 81,86,87 Lastly, the convection-enhanced delivery approach (CED) allows for intratumoral local drug injection via a catheter. Despite the invasive nature of the approach, CED has documented efficacy and safety with several therapeutic agents.…”

Section: Role Of Tgf-bmentioning

confidence: 99%

Inflammatory Mediators in Glioma Microenvironment Play a Dual Role in Gliomagenesis and Mesenchymal Stem Cell Homing: Implication for Cellular Therapy

Al‐kharboosh

Lara-Velazquez

Grewal

et al. 2020

Mayo Clinic Proceedings: Innovations, Quality & Outcomes

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Glioblastoma is the most aggressive malignant primary brain tumor, with a dismal prognosis and a devastating overall survival. Despite aggressive surgical resection and adjuvant treatment, average survival remains approximately 14.6 months. The brain tumor microenvironment is heterogeneous, comprising multiple populations of tumor, stromal, and immune cells. Tumor cells evade the immune system by suppressing several immune functions to enable survival. Gliomas release immunosuppressive and tumorsupportive soluble factors into the microenvironment, leading to accelerated cancer proliferation, invasion, and immune escape. Mesenchymal stem cells (MSCs) isolated from bone marrow, adipose tissue, or umbilical cord are a promising tool for cell-based therapies. One crucial mechanism mediating the therapeutic outcomes often seen in MSC application is their tropism to sites of injury. Furthermore, MSCs interact with host immune cells to regulate the inflammatory response, and data points to the possibility of using MSCs to achieve immunomodulation in solid tumors. Interleukin 1b, interleukin 6, tumor necrosis factor a, transforming growth factor b, and stromal cellederived factor 1 are notably up-regulated in glioblastoma and dually promote immune and MSC trafficking. Mesenchymal stem cells have widely been regarded as hypoimmunogenic, enabling this cell-based administration across major histocompatibility barriers. In this review, we will highlight (1) the bidirectional communication of glioma cells and tumorassociated immune cells, (2) the inflammatory mediators enabling leukocytes and transplantable MSC migration, and (3) review preclinical and human clinical trials using MSCs as delivery vehicles. Mesenchymal stem cells possess innate abilities to migrate great distances, cross the blood-brain barrier, and communicate with surrounding cells, all of which make them desirable "Trojan horses" for brain cancer therapy.

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“…Due to this technical limitation, we failed to choose a lower concentration at the onset. In addition, for in‐vivo studies, unbound concentration ratios in blood should also be considered . STL has an extremely high plasma protein binding ratio, and thus, only a small proportion of free drug penetrates the brain .…”

Section: Discussionmentioning

confidence: 99%

In-vitro and in situ assessment of the efflux of five antidepressants by breast cancer resistance protein

Feng

Zheng

Tang

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Antidepressants need to penetrate the blood-brain barrier (BBB) to exert their functions in the central nervous system. Breast cancer resistance protein (BCRP), an efflux transporter abundantly expressed in the BBB, prevents the accumulation of many drugs in the brain. This study aimed to identify whether five commonly used antidepressants (sertraline, duloxetine, fluoxetine, amitriptyline and mirtazapine) are BCRP substrates. Methods A combination of bidirectional transport and intracellular accumulation experiments was conducted on BCRP-overexpressing MDCKII and wildtype (WT) cells, and in situ brain perfusion was conducted in rats. Key findings The bidirectional transport study revealed that the net efflux ratio (NER) of sertraline reached 2.08 but decreased to 1.06 when co-incubated with Ko143, a selective BCRP inhibitor. Conversely, the other four antidepressants did not appear to be BCRP substrates, due to their low NER values (<1.5). The accumulation of sertraline in MDCKII-BCRP cells was significantly lower than that in MDCKII-WT cells. The presence of Ko143 significantly increased the sertraline accumulation in MDCKII-BCRP cells but not in MDCKII-WT cells. Brain perfusion showed that the permeability of 1 and 5 lM sertraline was significantly higher in the presence of Ko143. Conclusions Taken together, BCRP is involved in sertraline efflux.

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Prediction of brain:blood unbound concentration ratios in CNS drug discovery employing in silico and in vitro model systems

Cited by 58 publications

References 108 publications

Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico

Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico

Inflammatory Mediators in Glioma Microenvironment Play a Dual Role in Gliomagenesis and Mesenchymal Stem Cell Homing: Implication for Cellular Therapy

In-vitro and in situ assessment of the efflux of five antidepressants by breast cancer resistance protein

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