Daniel S. Murrell

Prediction of the potency of mammalian cyclooxygenase inhibitors with ensemble proteochemometric modeling

AbstractCyclooxygenases (COX) are present in the body in two isoforms, namely: COX-1, constitutively expressed, and COX-2, induced in physiopathological conditions such as cancer or chronic inflammation. The inhibition of COX with non-steroideal anti-inflammatory drugs (NSAIDs) is the most widely used treatment for chronic inflammation despite the adverse effects associated to prolonged NSAIDs intake. Although selective COX-2 inhibition has been shown not to palliate all adverse effects (e.g. cardiotoxicity), there are still niche populations which can benefit from selective COX-2 inhibition. Thus, capitalizing on bioactivity data from both isoforms simultaneously would contribute to develop COX inhibitors with better safety profiles. We applied ensemble proteochemometric modeling (PCM) for the prediction of the potency of 3,228 distinct COX inhibitors on 11 mammalian cyclooxygenases. Ensemble PCM models (R0test2=0.65

Proteochemometric modeling in a Bayesian framework.

R_{0\ test}^{2}=0.65

How do metabolites differ from their parent molecules and how are they excreted

, and RMSEtest = 0.71) outperformed models exclusively trained on compound (R0test2=0.17

Chemically Aware Model Builder (camb): an R package for property and bioactivity modelling of small molecules.

R_{0\ test}^{2}=0.17

R2-equitability is satisfiable.

, and RMSEtest = 1.09) or protein descriptors (R0test2=0.16

Discovering General Multidimensional Associations.

R_{0\ test}^{2}=0.16

Applications of proteochemometrics - from species extrapolation to cell line sensitivity modelling

and RMSEtest = 1.10) on the test set. Moreover, PCM predicted COX potency for 1,086 selective and non-selective COX inhibitors with R0test2=0.59

Quantifying the shifts in physicochemical property space introduced by the metabolism of small organic molecules

R_{0\ test}^{2}=0.59

Cancer Cell Line Profiler (CCLP): a webserver for the prediction of compound activity across the NCI60 panel

and RMSEtest = 0.76. These values are in agreement with the maximum and minimum achievable R0test2

Improving the prediction of organism-level toxicity through integration of chemical, protein target and cytotoxicity qHTS data

R_{0\ test}^{2}