Format

Send to

Choose Destination
Int J Mol Sci. 2018 Mar 30;19(4). pii: E1040. doi: 10.3390/ijms19041040.

MetStabOn-Online Platform for Metabolic Stability Predictions.

Author information

1
Institute of Pharmacology, Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna Street 12, 31-343 Kraków, Poland. smusz@if-pan.krakow.pl.
2
Institute of Pharmacology, Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna Street 12, 31-343 Kraków, Poland. rafal.kafel@gmail.com.

Abstract

Metabolic stability is an important parameter to be optimized during the complex process of designing new active compounds. Tuning this parameter with the simultaneous maintenance of a desired compound's activity is not an easy task due to the extreme complexity of metabolic pathways in living organisms. In this study, the platform for in silico qualitative evaluation of metabolic stability, expressed as half-lifetime and clearance was developed. The platform is based on the application of machine learning methods and separate models for human, rat and mouse data were constructed. The compounds' evaluation is qualitative and two types of experiments can be performed-regression, which is when the compound is assigned to one of the metabolic stability classes (low, medium, high) on the basis of numerical value of the predicted half-lifetime, and classification, in which the molecule is directly assessed as low, medium or high stability. The results show that the models have good predictive power, with accuracy values over 0.7 for all cases, for Sequential Minimal Optimization (SMO), k-nearest neighbor (IBk) and Random Forest algorithms. Additionally, for each of the analyzed compounds, 10 of the most similar structures from the training set (in terms of Tanimoto metric similarity) are identified and made available for download as separate files for more detailed manual inspection. The predictive power of the models was confronted with the external dataset, containing metabolic stability assessment via the GUSAR software, leading to good consistency of results for SMOreg and Naïve Bayes (~0.8 on average). The tool is available online.

KEYWORDS:

ChEMBL database; classification; machine learning; metabolic stability; regression

PMID:
29601530
PMCID:
PMC5979396
DOI:
10.3390/ijms19041040
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center