title: Using open source computational tools for predicting human metabolic stability and additional absorption, distribution, metabolism, excretion, and toxicity properties.
abstract: Ligand-based computational models could be more readily shared between researchers and organizations if they were generated with open source molecular descriptors [e.g., chemistry development kit (CDK)] and modeling algorithms, because this would negate the requirement for proprietary commercial software. We initially evaluated open source descriptors and model building algorithms using a training set of approximately 50,000 molecules and a test set of approximately 25,000 molecules with human liver microsomal metabolic stability data. A C5.0 decision tree model demonstrated that CDK descriptors together with a set of Smiles Arbitrary Target Specification (SMARTS) keys had good statistics [κ = 0.43, sensitivity = 0.57, specificity = 0.91, and positive predicted value (PPV) = 0.64], equivalent to those of models built with commercial Molecular Operating Environment 2D (MOE2D) and the same set of SMARTS keys (κ = 0.43, sensitivity = 0.58, specificity = 0.91, and PPV = 0.63). Extending the dataset to ∼193,000 molecules and generating a continuous model using Cubist with a combination of CDK and SMARTS keys or MOE2D and SMARTS keys confirmed this observation. When the continuous predictions and actual values were binned to get a categorical score we observed a similar κ statistic (0.42). The same combination of descriptor set and modeling method was applied to passive permeability and P-glycoprotein efflux data with similar model testing statistics. In summary, open source tools demonstrated predictive results comparable to those of commercial software with attendant cost savings. We discuss the advantages and disadvantages of open source descriptors and the opportunity for their use as a tool for organizations to share data precompetitively, avoiding repetition and assisting drug discovery.
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut, USA.
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Gupta
authors.forename: Eric M
authors.initials: EM
authors.lastname: Gifford
authors.forename: Ted
authors.initials: T
authors.lastname: Liston
authors.forename: Chris L
authors.initials: CL
authors.lastname: Waller
authors.forename: Moses
authors.initials: M
authors.lastname: Hohman
authors.forename: Barry A
authors.initials: BA
authors.lastname: Bunin
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
mesh_terms: D000042:Absorption; D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011237:Predictive Value of Tests; D012984:Software; D012995:Solubility; D014018:Tissue Distribution; D014116:Toxicology / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations