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Critical evaluation of human oral bioavailability for pharmaceutical drugs by using various cheminformatics approaches.

ABSTRACT: PURPOSE:Oral bioavailability (%F) is a key factor that determines the fate of a new drug in clinical trials. Traditionally, %F is measured using costly and time-consuming experimental tests. Developing computational models to evaluate the %F of new drugs before they are synthesized would be beneficial in the drug discovery process. METHODS:We employed Combinatorial Quantitative Structure-Activity Relationship approach to develop several computational %F models. We compiled a %F dataset of 995 drugs from public sources. After generating chemical descriptors for each compound, we used random forest, support vector machine, k nearest neighbor, and CASE Ultra to develop the relevant QSAR models. The resulting models were validated using five-fold cross-validation. RESULTS:The external predictivity of %F values was poor (R(2)?=?0.28, n?=?995, MAE?=?24), but was improved (R(2)?=?0.40, n?=?362, MAE?=?21) by filtering unreliable predictions that had a high probability of interacting with MDR1 and MRP2 transporters. Furthermore, classifying the compounds according to the %F values (%F?

SUBMITTER: Kim MT

PROVIDER: S-EPMC3955412 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Critical evaluation of human oral bioavailability for pharmaceutical drugs by using various cheminformatics approaches.

Kim Marlene T MT Sedykh Alexander A Chakravarti Suman K SK Saiakhov Roustem D RD Zhu Hao H

Pharmaceutical research 20131203 4

<h4>Purpose</h4>Oral bioavailability (%F) is a key factor that determines the fate of a new drug in clinical trials. Traditionally, %F is measured using costly and time-consuming experimental tests. Developing computational models to evaluate the %F of new drugs before they are synthesized would be beneficial in the drug discovery process.<h4>Methods</h4>We employed Combinatorial Quantitative Structure-Activity Relationship approach to develop several computational %F models. We compiled a %F da ...[more]

PMID: 24306326

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Project description:The diversity of hundreds of thousands of potential organic pollutants and the lack of (publicly available) information about many of them is a huge challenge for environmental sciences, engineering, and regulation. Suspect screening based on high-resolution liquid chromatography-mass spectrometry (LC-HRMS) has enormous potential to help characterize the presence of these chemicals in our environment, enabling the detection of known and newly emerging pollutants, as well as their potential transformation products (TPs). Here, suspect list creation (focusing on pesticides relevant for Luxembourg, incorporating data sources in 4 languages) was coupled to an automated retrieval of related TPs from PubChem based on high confidence suspect hits, to screen for pesticides and their TPs in Luxembourgish river samples. A computational workflow was established to combine LC-HRMS analysis and pre-screening of the suspects (including automated quality control steps), with spectral annotation to determine which pesticides and, in a second step, their related TPs may be present in the samples. The data analysis with Shinyscreen (https://gitlab.lcsb.uni.lu/eci/shinyscreen/), an open source software developed in house, coupled with custom-made scripts, revealed the presence of 162 potential pesticide masses and 96 potential TP masses in the samples. Further identification of these mass matches was performed using the open source approach MetFrag (https://msbi.ipb-halle.de/MetFrag/). Eventual target analysis of 36 suspects resulted in 31 pesticides and TPs confirmed at Level-1 (highest confidence), and five pesticides and TPs not confirmed due to different retention times. Spatio-temporal analysis of the results showed that TPs and pesticides followed similar trends, with a maximum number of potential detections in July. The highest detections were in the rivers Alzette and Mess and the lowest in the Sûre and Eisch. This study (a) added pesticides, classification information and related TPs into the open domain, (b) developed automated open source retrieval methods - both enhancing FAIRness (Findability, Accessibility, Interoperability and Reusability) of the data and methods; and (c) will directly support "L'Administration de la Gestion de l'Eau" on further monitoring steps in Luxembourg.

Dataset Information

Critical evaluation of human oral bioavailability for pharmaceutical drugs by using various cheminformatics approaches.

Publications

Critical evaluation of human oral bioavailability for pharmaceutical drugs by using various cheminformatics approaches.

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