Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches

Kim, Marlene T.; Sedykh, Alexander; Chakravarti, Suman K.; Saiakhov, Roustem; Zhu, Hao

doi:10.1007/s11095-013-1222-1

Cited by 91 publications

(90 citation statements)

References 40 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our previous studies showed that using hybrid descriptors, which are the combinations of chemical and biological descriptors, showed superior results compared to traditional QSAR models only based on chemical descriptors (23,37,38). The predictivity of hybrid modes is higher than the traditional QSAR models and the analysis of chemical-biological descriptor patterns in resulting models can reveal the relevant chemical biological mechanisms of target activities.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Developing Enhanced Blood–Brain Barrier Permeability Models: Integrating External Bio-Assay Data in QSAR Modeling

et al. 2015

Self Cite

View full text Add to dashboard Cite

Purpose Experimental Blood–Brain Barrier (BBB) permeability models for drug molecules are expensive and time-consuming. As alternative methods, several traditional Quantitative Structure-Activity Relationship (QSAR) models have been developed previously. In this study, we aimed to improve the predictivity of traditional QSAR BBB permeability models by employing relevant public bio-assay data in the modeling process. Methods We compiled a BBB permeability database consisting of 439 unique compounds from various resources. The database was split into a modeling set of 341 compounds and a validation set of 98 compounds. Consensus QSAR modeling workflow was employed on the modeling set to develop various QSAR models. A five-fold cross-validation approach was used to validate the developed models, and the resulting models were used to predict the external validation set compounds. Furthermore, we used previously published membrane transporter models to generate relevant transporter profiles for target compounds. The transporter profiles were used as additional biological descriptors to develop hybrid QSAR BBB models. Results The consensus QSAR models have R2=0.638 for fivefold cross-validation and R2=0.504 for external validation. The consensus model developed by pooling chemical and transporter descriptors showed better predictivity (R2=0.646 for five-fold cross-validation and R2=0.526 for external validation). Moreover, several external bio-assays that correlate with BBB permeability were identified using our automatic profiling tool. Conclusions The BBB permeability models developed in this study can be useful for early evaluation of new compounds (e.g., new drug candidates). The combination of chemical and biological descriptors shows a promising direction to improve the current traditional QSAR models.

show abstract

Section: Resultsmentioning

confidence: 99%

“…An extra consensus QSAR model was then generated by averaging predictions of the three individual models. The development and application of consensus QSAR models have been reported in our previous publications (21–23). …”

Section: Methodsmentioning

confidence: 99%

Developing Enhanced Blood–Brain Barrier Permeability Models: Integrating External Bio-Assay Data in QSAR Modeling

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…The rule states that an orally active drug has no more than one violation of the following criteria: (i) no more than five hydrogen bond donors, (ii) no more than ten hydrogen bond acceptors, (iii) a molecular mass less than 500 Da, and, finally, (iv) an octanol-water partition coefficient logP not greater than 5 (Lipinski et al 1997). This rule has been subsequently completed or amended by many authors to try to improve prediction models (Bergstrom et al 2014, Bhal et al 2007, Deconinck et al 2007, Gozalbes et al 2011, Kim et al 2014, Kujawski et al 2012, Palm et al 1997, Talevi et al 2011, van de Waterbeemd et al 2003, Veber et al 2002, Winiwarter et al 2003, Winiwarter et al 1998. To our knowledge, this approach was never or rarely developed in plant physiology to evaluate the capacity of a chemical to passively cross the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Modifications of the chemical structure of phenolics differentially affect physiological activities in pulvinar cells of Mimosa pudica L. II. Influence of various molecular properties in relation to membrane transport

Rocher

Roblin

Chollet

2016

Environ Sci Pollut Res

View full text Add to dashboard Cite

Early prediction of compound absorption by cells is of considerable importance in the building of an integrated scheme describing the impact of a compound on intracellular biological processes. In this scope, we study the structure-activity relationships of several benzoic acid-related phenolics which are involved in many plant biological phenomena (growth, flowering, allelopathy, defense processes). Using the partial least squares (PLS) regression method, the impact of molecular descriptors that have been shown to play an important role concerning the uptake of pharmacologically active compounds by animal cells was analyzed in terms of the modification of membrane potential, variations in proton flux, and inhibition of the osmocontractile reaction of pulvinar cells of Mimosa pudica leaves. The hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA), polar surface area (PSA), halogen ratio (Hal ratio), number of rotatable bonds (FRB), molar volume (MV), molecular weight (MW), and molar refractivity (MR) were considered in addition to two physicochemical properties (logD and the amount of non-dissociated form in relation to pKa). HBD + HBA and PSA predominantly impacted the three biological processes compared to the other descriptors. The coefficient of determination in the quantitative structure-activity relationship (QSAR) models indicated that a major part of the observed seismonasty inhibition and proton flux modification can be explained by the impact of these descriptors, whereas this was not the case for membrane potential variations. These results indicate that the transmembrane transport of the compounds is a predominant component. An increasing number of implicated descriptors as the biological processes become more complex may reflect their impacts on an increasing number of sites in the cell. The determination of the most efficient effectors may lead to a practical use to improve drugs in the control of microbial attacks on plants.

show abstract

“…All users can download publicly available models from Chembench, while only registered users can save, store, and download their personal models on Chembench. Currently, there are 124 publicly available predictors on Chembench that can either be downloaded or used for virtual screening (See Prediction), including, for example, predictors of the human intestinal transporter inhibition, 41 human oral bioavailability, 42 human plasma protein binding, 43 stress response and nuclear receptor signaling toxicity assays. 44 A full list of publicly available predictors can be found in the Supporting Information.…”

Section: Chembench Environmentmentioning

confidence: 99%

Chembench: A Publicly Accessible, Integrated Cheminformatics Portal

Capuzzi

Sang-June

Lam

et al. 2017

J. Chem. Inf. Model.

View full text Add to dashboard Cite

The enormous increase in the amount of publicly available chemical genomics data and the growing emphasis on data sharing and open science mandates that cheminformaticians make their models publicly available for broad use by the scientific community. Chembench is one of the first publicly-accessible, integrated cheminformatics Web portals. It has been extensively used by researchers from different fields for curation, visualization, analysis, and modeling of chemogenomics data. Since its launch in 2008, Chembench has been accessed more than 1 million times by more than 5K users from a total of 98 countries. We report on the recent updates and improvements that increase the simplicity of use, computational efficiency, accuracy, and accessibility of a broad range of tools and services for computer-assisted drug design and computational toxicology available on Chembench. Chembench remains freely accessible at https://chembench.mml.unc.edu

show abstract

Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches

Cited by 91 publications

References 40 publications

Developing Enhanced Blood–Brain Barrier Permeability Models: Integrating External Bio-Assay Data in QSAR Modeling

Developing Enhanced Blood–Brain Barrier Permeability Models: Integrating External Bio-Assay Data in QSAR Modeling

Modifications of the chemical structure of phenolics differentially affect physiological activities in pulvinar cells of Mimosa pudica L. II. Influence of various molecular properties in relation to membrane transport

Chembench: A Publicly Accessible, Integrated Cheminformatics Portal

Contact Info

Product

Resources

About