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Biomedical subjects

Han van de Waterbeemd

Publications and source records attributed to Han van de Waterbeemd.

7 recordsLinked to original sources
PubMed2005

Biosensor analysis of the interaction between drug compounds and liposomes of different properties; a two-dimensional characterization tool for estimation of membrane absorption.

The interactions between 78 drug compounds and immobilised liposomes were investigated using an assay based on surface plasmon resonance technology. The drugs were screened at a single concentration and allowed to interact simultaneously with two different types of liposomes. When the drug-liposome responses are plotted against one another they generally fall into three distinct bands: low response-low percent fraction absorbed in humans (Fa), medium response-medium Fa, and high response-high Fa. For drugs with medium to high Fa values, basic compounds could be resolved from acidic and neutral compounds to a large extent. This technique has the potential to be utilized as a screening tool for binning novel compounds into low, medium, or high Fa based on a simple experimental measurement. The assay was applied to 11 kinase inhibitors, 9 thrombin inhibitors, and 11 carbonic anhydrase inhibitors highlighting a subset that may have incomplete intestinal absorption (low to medium Fa). Assay conditions were optimized making the assay suitable for routine analysis and for compound characterization early in drug discovery where solubility may be an issue.

Absorption↗
PubMed2005

Which in vitro screens guide the prediction of oral absorption and volume of distribution?

The development of medium to high-throughput in vitro screening of ADME (Absorption, Distribution, Metabolism, Excretion) properties has been the reply to higher demands on drug metabolism scientists to cope with progress in chemistry and biology. Two areas will be discussed here, namely screens for oral absorption and for volume of distribution. The prediction of these human pharmacokinetic parameters can be based on proper combination of simple physicochemical measurements. In the future in vitro screens most likely will be combined with in silico assessments of various ADME properties leading to the concept of in combo screening in drug discovery.

Administration, Oral↗
PubMed2003

Prediction of oral bioavailability by adaptive fuzzy partitioning.

An adaptive fuzzy partition (AFP) algorithm was applied on two bioavailability data sets subdivided into four ranges of activity. A large set of molecular descriptors was tested and the most relevant parameters were selected with help of a procedure based on genetic algorithm concepts and stepwise method. After building several AFP models on a training set, the best ones were able to predict correctly 75% of the validation set compounds. Furthermore, an improvement of about 15% in the validation results was got, on the same data set, as regard to other prediction methods. The importance to work with data sets including a large molecular diversity, and to use tools able to manage it, was also shown. The prediction power was increased up to 25% employing a data set with a better-optimised molecular diversity.

Administration, Oral↗
PubMed2003

ADMET in silico modelling: towards prediction paradise?

Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chemistry and high-throughput screening have significantly increased the number of compounds for which early data on absorption, distribution, metabolism, excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.

Animals↗
PubMed2002

High-throughput and in silico techniques in drug metabolism and pharmacokinetics.

The high-throughput screening (HTS) of large proprietary compound collections and combinatorial libraries has increased the pressure on gathering pharmacokinetic and drug metabolism data as early as possible. Properties related to absorption, distribution, metabolism and excretion (ADME) can be estimated by a range of in vivo and in vitro methods, most of which are now available or under development in high(er)-throughput modus. In addition, progress has been made in in silico methods using various quantitaTive structure-activity relationship (QSAR) and molecular modeling techniques that employ a range of recently introduced descriptors tailored to e-ADME. These in silico approaches are promising filters for virtual libraries to aid synthesis as well as the selection of compounds for acquisition and screening in the early stages of drug discovery.

Absorption↗