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Prediction of overall in vitro microsomal stability of drug candidates based on molecular modeling and support vector machines. Case study of novel arylpiperazines derivatives.

Ulenberg S, Belka M, Król M, Herold F, Hewelt-Belka W, Kot-Wasik A, Bączek T - PLoS ONE (2015)

Bottom Line: The results indicated that the application of one of the most advanced chemometric techniques combined with a simple and quick in vitro procedure and LC-MS analysis provides a novel and valuable tool for predicting metabolic half-life values.Given the reduced time and simplicity of analysis, together with the accuracy of the predictions obtained, this is a valid approach for predicting metabolic stability using structural data.The performance of the DFT-SVM-based approach provides an opportunity to implement it in a standard drug development pipeline.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland.

ABSTRACT
Other than efficacy of interaction with the molecular target, metabolic stability is the primary factor responsible for the failure or success of a compound in the drug development pipeline. The ideal drug candidate should be stable enough to reach its therapeutic site of action. Despite many recent excellent achievements in the field of computational methods supporting drug metabolism studies, a well-recognized procedure to model and predict metabolic stability quantitatively is still lacking. This study proposes a workflow for developing quantitative metabolic stability-structure relationships, taking a set of 30 arylpiperazine derivatives as an example. The metabolic stability of the compounds was assessed in in vitro incubations in the presence of human liver microsomes and NADPH and subsequently quantified by liquid chromatography-mass spectrometry (LC-MS). Density functional theory (DFT) calculations were used to obtain 30 models of the molecules, and Dragon software served as a source of structure-based molecular descriptors. For modeling structure-metabolic stability relationships, Support Vector Machines (SVM), a non-linear machine learning technique, were found to be more effective than a regression technique, based on the validation parameters obtained. Moreover, for the first time, general sites of metabolism for arylpiperazines bearing the 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione system were defined by analysis of Q-TOF-MS/MS spectra. The results indicated that the application of one of the most advanced chemometric techniques combined with a simple and quick in vitro procedure and LC-MS analysis provides a novel and valuable tool for predicting metabolic half-life values. Given the reduced time and simplicity of analysis, together with the accuracy of the predictions obtained, this is a valid approach for predicting metabolic stability using structural data. The approach presented provides a novel, comprehensive and reliable tool for investigating metabolic stability, factors that affect it, and the proposed structures of metabolites at the same time. The performance of the DFT-SVM-based approach provides an opportunity to implement it in a standard drug development pipeline.

No MeSH data available.


Related in: MedlinePlus

Structures of studied compounds.A) General structure of compounds 1–17 B) General structure of compounds 18–30 C) Structure of compound 25
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pone.0122772.g001: Structures of studied compounds.A) General structure of compounds 1–17 B) General structure of compounds 18–30 C) Structure of compound 25

Mentions: The general structure of the studied arylpiperazine derivatives is shown on Fig 1. Table 1 presents average half-life values in minutes, for both studied derivatives and most popular arylpiperazine drug available on market—buspirone. After 30 minutes of incubation, all of the derivatives were metabolized, as evidenced by the parent compound peak areas for all compounds existing at less than 30% of the starting peak areas (Fig 2). As shown in Fig 3, after transforming the peak area/internal standard peak area ratio using a logarithmic function, a linear dependence was achieved, according to Equation 1. To evaluate the biotransformation half-life, only the linear part of the plot was used. The values obtained for t0.5 ranged from 3 to 9 minutes. No clear rules can be found regarding the relationship between particular substituents and the obtained half-life values.


Prediction of overall in vitro microsomal stability of drug candidates based on molecular modeling and support vector machines. Case study of novel arylpiperazines derivatives.

Ulenberg S, Belka M, Król M, Herold F, Hewelt-Belka W, Kot-Wasik A, Bączek T - PLoS ONE (2015)

Structures of studied compounds.A) General structure of compounds 1–17 B) General structure of compounds 18–30 C) Structure of compound 25
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380424&req=5

pone.0122772.g001: Structures of studied compounds.A) General structure of compounds 1–17 B) General structure of compounds 18–30 C) Structure of compound 25
Mentions: The general structure of the studied arylpiperazine derivatives is shown on Fig 1. Table 1 presents average half-life values in minutes, for both studied derivatives and most popular arylpiperazine drug available on market—buspirone. After 30 minutes of incubation, all of the derivatives were metabolized, as evidenced by the parent compound peak areas for all compounds existing at less than 30% of the starting peak areas (Fig 2). As shown in Fig 3, after transforming the peak area/internal standard peak area ratio using a logarithmic function, a linear dependence was achieved, according to Equation 1. To evaluate the biotransformation half-life, only the linear part of the plot was used. The values obtained for t0.5 ranged from 3 to 9 minutes. No clear rules can be found regarding the relationship between particular substituents and the obtained half-life values.

Bottom Line: The results indicated that the application of one of the most advanced chemometric techniques combined with a simple and quick in vitro procedure and LC-MS analysis provides a novel and valuable tool for predicting metabolic half-life values.Given the reduced time and simplicity of analysis, together with the accuracy of the predictions obtained, this is a valid approach for predicting metabolic stability using structural data.The performance of the DFT-SVM-based approach provides an opportunity to implement it in a standard drug development pipeline.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland.

ABSTRACT
Other than efficacy of interaction with the molecular target, metabolic stability is the primary factor responsible for the failure or success of a compound in the drug development pipeline. The ideal drug candidate should be stable enough to reach its therapeutic site of action. Despite many recent excellent achievements in the field of computational methods supporting drug metabolism studies, a well-recognized procedure to model and predict metabolic stability quantitatively is still lacking. This study proposes a workflow for developing quantitative metabolic stability-structure relationships, taking a set of 30 arylpiperazine derivatives as an example. The metabolic stability of the compounds was assessed in in vitro incubations in the presence of human liver microsomes and NADPH and subsequently quantified by liquid chromatography-mass spectrometry (LC-MS). Density functional theory (DFT) calculations were used to obtain 30 models of the molecules, and Dragon software served as a source of structure-based molecular descriptors. For modeling structure-metabolic stability relationships, Support Vector Machines (SVM), a non-linear machine learning technique, were found to be more effective than a regression technique, based on the validation parameters obtained. Moreover, for the first time, general sites of metabolism for arylpiperazines bearing the 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione system were defined by analysis of Q-TOF-MS/MS spectra. The results indicated that the application of one of the most advanced chemometric techniques combined with a simple and quick in vitro procedure and LC-MS analysis provides a novel and valuable tool for predicting metabolic half-life values. Given the reduced time and simplicity of analysis, together with the accuracy of the predictions obtained, this is a valid approach for predicting metabolic stability using structural data. The approach presented provides a novel, comprehensive and reliable tool for investigating metabolic stability, factors that affect it, and the proposed structures of metabolites at the same time. The performance of the DFT-SVM-based approach provides an opportunity to implement it in a standard drug development pipeline.

No MeSH data available.


Related in: MedlinePlus