title: In silico prediction of pharmaceutical degradation pathways: a benchmarking study.
abstract: Zeneth is a new software application capable of predicting degradation products derived from small molecule active pharmaceutical ingredients. This study was aimed at understanding the current status of Zeneth's predictive capabilities and assessing gaps in predictivity. Using data from 27 small molecule drug substances from five pharmaceutical companies, the evolution of Zeneth predictions through knowledge base development since 2009 was evaluated. The experimentally observed degradation products from forced degradation, accelerated, and long-term stability studies were compared to Zeneth predictions. Steady progress in predictive performance was observed as the knowledge bases grew and were refined. Over the course of the development covered within this evaluation, the ability of Zeneth to predict experimentally observed degradants increased from 31% to 54%. In particular, gaps in predictivity were noted in the areas of epimerizations, N-dealkylation of N-alkylheteroaromatic compounds, photochemical decarboxylations, and electrocyclic reactions. The results of this study show that knowledge base development efforts have increased the ability of Zeneth to predict relevant degradation products and aid pharmaceutical research. This study has also provided valuable information to help guide further improvements to Zeneth and its knowledge base.
authors.affiliation: Projects, Clinical Platforms and Sciences, GlaxoSmithKline, 2301 Renaissance Boulevard, RN0320, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kleinman
authors.forename: Steven W
authors.initials: SW
authors.lastname: Baertschi
authors.forename: Karen M
authors.initials: KM
authors.lastname: Alsante
authors.forename: Darren L
authors.initials: DL
authors.lastname: Reid
authors.forename: Mark D
authors.initials: MD
authors.lastname: Mowery
authors.forename: Roman
authors.initials: R
authors.lastname: Shimanovich
authors.forename: Chris
authors.initials: C
authors.lastname: Foti
authors.forename: William K
authors.initials: WK
authors.lastname: Smith
authors.forename: Dan W
authors.initials: DW
authors.lastname: Reynolds
authors.forename: Marcela
authors.initials: M
authors.lastname: Nefliu
authors.forename: Martin A
authors.initials: MA
authors.lastname: Ott
mesh_terms: D019985:Benchmarking; D003198:Computer Simulation; D004355:Drug Stability; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D012984:Software
chemical_list: D004364:Pharmaceutical Preparations
keywords: Zeneth benchmark; degradation pathways; expert system; knowledge base; pharmaceutical forced degradation; prediction; stress testing