Technical Challenges and Recent Advances of Implementing Comprehensive ADMET Tools in Drug Discovery

Wang, Jianling; Bell, Leslie

doi:10.1002/9781118180778.ch9

Cited by 3 publications

(2 citation statements)

References 127 publications

(143 reference statements)

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“…In current industrial practise, a new effort is being made by integrating the pharmacokinetic profiling in parallel with the pharmacological screening to maximise the chances for selecting superior drug candidates [6]. In this context, a variety of highly accurate and HTS techniques has been developed for the early evaluation of absorption, distribution, metabolism, excretion, and toxicity properties of compounds of interest [7]. For the early prediction of absorption, PAMPA is one of the most frequently used in vitro models [5,8].…”

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confidence: 99%

Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA)

et al. 2016

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At the early drug discovery stage, the high-throughput parallel artificial membrane permeability assay is one of the most frequently used in vitro models to predict transcellular passive absorption. While thousands of new chemical entities have been screened with the parallel artificial membrane permeability assay, in general, permeation properties of natural products have been scarcely evaluated. In this study, the parallel artificial membrane permeability assay through a hexadecane membrane was used to predict the passive intestinal absorption of a representative set of frequently occurring natural products. Since natural products are usually ingested for medicinal use as components of complex extracts in traditional herbal preparations or as phytopharmaceuticals, the applicability of such an assay to study the constituents directly in medicinal crude plant extracts was further investigated. Three representative crude plant extracts with different natural product compositions were chosen for this study. The first extract was composed of furanocoumarins (Angelica archangelica), the second extract included alkaloids (Waltheria indica), and the third extract contained flavonoid glycosides (Pueraria montana var. lobata). For each medicinal plant, the effective passive permeability values Pe (cm/s) of the main natural products of interest were rapidly calculated thanks to a generic ultrahigh-pressure liquid chromatography-UV detection method and because Pe calculations do not require knowing precisely the concentration of each natural product within the extracts. The original parallel artificial membrane permeability assay through a hexadecane membrane was found to keep its predictive power when applied to constituents directly in crude plant extracts provided that higher quantities of the extract were initially loaded in the assay in order to ensure suitable detection of the individual constituents of the extracts. Such an approach is thus valuable for the high-throughput, cost-effective, and early evaluation of passive intestinal absorption of active principles in medicinal plants. In phytochemical studies, obtaining effective passive permeability values of pharmacologically active natural products is important to predict if natural products showing interesting activities in vitro may have a chance to reach their target in vivo.

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confidence: 99%

Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA)

et al. 2016

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“…The model was then trained using the optimal hyperparameters and evaluated using the Pearson R 2 score (Figure 1B ‐ D ). It is worth mentioning that we used the data set of Caco‐2 assay for model training, in cases where LogP app (cm s −1 ) > −5.5 [LogP app (nm s −1 ) > 1.5] measured in this assay is considered a necessary indicator of passive diffusion, [ 39 , 40 ] we set a B score of 1.5 as a criterion for whether payload has a potential bystander effect.…”

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Rational Identification of Novel Antibody‐Drug Conjugate with High Bystander Killing Effect against Heterogeneous Tumors

Guo,

Shen,

Zhao

et al. 2024

Advanced Science

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Bystander‐killing payloads can significantly overcome the tumor heterogeneity issue and enhance the clinical potential of antibody‐drug conjugates (ADC), but the rational design and identification of effective bystander warheads constrain the broader implementation of this strategy. Here, graph attention networks (GAT) are constructed for a rational bystander killing scoring model and ADC construction workflow for the first time. To generate efficient bystander‐killing payloads, this model is utilized for score‐directed exatecan derivatives design. Among them, Ed9, the most potent payload with satisfactory permeability and bioactivity, is further used to construct ADC. Through linker optimization and conjugation, novel ADCs are constructed that perform excellent anti‐tumor efficacy and bystander‐killing effect in vivo and in vitro. The optimal conjugate T‐VEd9 exhibited therapeutic efficacy superior to DS‐8201 against heterogeneous tumors. These results demonstrate that the effective scoring approach can pave the way for the discovery of novel ADC with promising bystander payloads to combat tumor heterogeneity.

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Chapter 2 Solubility Determinations for Pharmaceutical API

Asare-Addo¹,

Conway²

2017

Poorly Soluble Drugs

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Technical Challenges and Recent Advances of Implementing Comprehensive ADMET Tools in Drug Discovery

Cited by 3 publications

References 127 publications

Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA)

Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA)

Rational Identification of Novel Antibody‐Drug Conjugate with High Bystander Killing Effect against Heterogeneous Tumors

Chapter 2 Solubility Determinations for Pharmaceutical API

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