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.
Highlights
Metabolic stability is a factor that often excludes potential drug candidates from any further studies
Conclusions drawn from this research stage can be used to design chemical modifications of the generation of new chemical entity (NCE), which can further improve their metabolic stability
In vitro studies allow for utilization of human enzymes, liver fractions or cells, providing data that reflects the in vivo situation without sacrificing a large number of animals and, importantly, minimizing costs
Summary
Metabolic stability is a factor that often excludes potential drug candidates from any further studies. Other studies show that in 1991, the major reasons for the failure of NCEs to obtain regulatory approval were inadequate metabolic and pharmacokinetic (PK) parameters [1]. This has lead to the development of new approaches dedicated to increasing the rate of NCE approval. One of these is an in vitro approach for early determination and prediction of the metabolism of a drug [2]. Of the many advantages this approach provides, one of the greatest is determination of a metabolic profile for the NCE earlier in the drug development process. In vitro studies allow for utilization of human enzymes, liver fractions or cells, providing data that reflects the in vivo situation without sacrificing a large number of animals and, importantly, minimizing costs
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