Cellular membrane affinity chromatography (CMAC) in drug discovery from complex natural matrices

Stephen, Cayman; Omri, Abdelfatteh El; Cieśla, Łukasz

doi:10.5599/admet.535

Cited by 4 publications

(5 citation statements)

References 46 publications

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“…However, as discussed earlier, BDNF cannot be used as a treatment option for neurological discorders . Therefore, alternative molecules have been explored to stimulate TrkB receptors, ,− such as 7,8-DHF. ,,, Thus, 7,8-DHF was used as a known binder to create an artificial mixture for initial screening. The artificial mixture consisted of equimolar concentrations (100 nM) of 7,8-DHF and non-binders: caffeic acid and rutin.…”

Section: Results and Discussionmentioning

confidence: 99%

“…High throughput screening techniques mainly focus on synthetic libraries of individual compounds and are not compatible with mixtures . Immobilization of transmembrane proteins on solid surfaces has been previously studied for the identification of drug candidates from complex natural matrices, but maintaining receptor activity has been challenging. ,,− …”

Section: Introductionmentioning

confidence: 99%

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Identification of TrkB Binders from Complex Matrices Using a Magnetic Drug Screening Nanoplatform

Arıtuluk

Horne

Adhikari

et al. 2021

ACS Appl. Bio Mater.

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Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) have been shown to play an important role in numerous neurological disorders, such as Alzheimer’s disease. The identification of biologically active compounds interacting with TrkB serves as a drug discovery strategy to identify drug leads for neurological disorders. Here, we report effective immobilization of functional TrkB on magnetic iron oxide nanoclusters, where TrkB receptors behave as “smart baits” to bind compounds from mixtures and magnetic nanoclusters enable rapid isolation through magnetic separation. The presence of the immobilized TrkB was confirmed by specific antibody labeling. Subsequently, the activity of the TrkB on iron oxide nanoclusters was evaluated with ATP/ADP conversion experiments using a known TrkB agonist. The immobilized TrkB receptors can effectively identify binders from mixtures containing known binders, synthetic small molecule mixtures, and Gotu Kola (Centella asiatica) plant extracts. The identified compounds were analyzed by an ultrahigh-performance liquid chromatography system coupled with a quadrupole time-of-flight mass spectrometer. Importantly, some of the identified TrkB binders from Gotu Kola plant extracts matched with compounds previously linked to neuroprotective effects observed for a Gotu Kola extract approved for use in a clinical trial. Our studies suggest that the possible therapeutic effects of the Gotu Kola plant extract in dementia treatment, at least partially, might be associated with compounds interacting with TrkB. The unique feature of this approach is its ability to fast screen potential drug leads using less explored transmembrane targets. This platform works as a drug-screening funnel at early stages of the drug discovery pipeline. Therefore, our approach will not only greatly benefit drug discovery processes using transmembrane proteins as targets but also allow for evaluation and validation of cellular pathways targeted by drug leads.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of TrkB Binders from Complex Matrices Using a Magnetic Drug Screening Nanoplatform

Arıtuluk

Horne

Adhikari

et al. 2021

ACS Appl. Bio Mater.

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“…The chromatographic technique provides an automated, high throughput and reliable measurement of important properties of the drug discovery compounds [ 25 ] that can be used to estimate later stage in vivo properties of compounds such as the volume of distribution, the unbound volume of distribution [ 26 ] and the drug efficiency [ 27 ]. Measurements can also estimate cell membrane partition and skin penetration of compounds based on chromatographic principles [ 28 , 29 ]. Various toxicity indicators have already been related to a compound’s physicochemical properties, including hERG inhibition and hepatotoxicity [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Prediction of hERG inhibition of drug discovery compounds using biomimetic HPLC measurements

Stergiopoulos

Tsopelas

Valkó³

2021

ADMET DMPK

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The major causes of failure of drug discovery compounds in clinics are the lack of efficacy and toxicity. To reduce late-stage failures in the drug discovery process, it is essential to estimate early the probability of adverse effects and potential toxicity. Cardiotoxicity is one of the most often observed problems related to a compound's inhibition of the hERG channel responsible for the potassium cation flux. Biomimetic HPLC methods can be used for the early screening of a compound's lipophilicity, protein binding and phospholipid partition. Based on the published hERG pIC50 data of 90 marketed drugs and their measured biomimetic properties, a model has been developed to predict the hERG inhibition using the measured binding of compounds to alpha-1-acid-glycoprotein (AGP) and immobilised artificial membrane (IAM). A representative test set of 16 compounds was carefully selected. The training set, involving the remaining compounds, served to establish the linear model. The mechanistic model supports the hypothesis that compounds have to traverse the cell membrane and bind to the hERG ion channel to cause the inhibition. The AGP and the hERG ion channel show structural similarity, as both bind positively charged compounds with strong shape selectivity. In contrast, a good IAM partition is a prerequisite for cell membrane traversal. For reasons of comparison, a corresponding model was derived by replacing the measured biomimetic properties with calculated physicochemical properties. The model established with the measured biomimetic binding properties proved to be superior and can explain over 70% of the variance of the hERG pIC50 values. ©2021 by the authors. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).

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“…Several papers belonging to the chromatography thematic issue will be published in the next issue of ADMET and DMPK including the papers of Ciesla et al [8], Tsopelas et al [9] and Caron et al [10].…”

mentioning

confidence: 99%

“…Lukasz Ciesla and his colleagues at the University of Alabama, USA have presented a new and innovative application of the immobilized artificial membrane stationary phase to bind membrane receptors on the surface called cellular membrane affinity chromatography (CMAC) that can enable the "fishing out" of potent molecules from complex mixtures [8].…”

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confidence: 99%

Chromatographic technique to support ADMET&DMPK in early drug discovery

Valkó¹

2018

ADMET DMPK

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The drug discovery process usually involves the discovery of a potent new chemical entity which has shown some activity on a target that is believed to be relevant in a certain type of disease. However, the structure and property of these putative drug molecules may have to be modified in order to ensure that they are able to exert the desired in vivo pharmacological effect. The candidate molecules usually have to be absorbed from the gastrointestinal system and therefore they must show appropriate solubility and permeability to be able to reach the target enzyme in vivo with a sufficient free biophase concentration at the site of action. This means that the physicochemical properties and the protein and phospholipid binding has to be optimized in order to achieve the desired in vivo ADMET and DMPK profile. The ADME studies usually require animal experiments or the use of biological samples, for example tissues which is expensive and involves time-consuming procedures. New technologies and approaches can accelerate this process.

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Cellular membrane affinity chromatography (CMAC) in drug discovery from complex natural matrices

Cited by 4 publications

References 46 publications

Identification of TrkB Binders from Complex Matrices Using a Magnetic Drug Screening Nanoplatform

Identification of TrkB Binders from Complex Matrices Using a Magnetic Drug Screening Nanoplatform

Prediction of hERG inhibition of drug discovery compounds using biomimetic HPLC measurements

Chromatographic technique to support ADMET&DMPK in early drug discovery

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