title: Prediction of PARP Inhibition with Proteochemometric Modelling and Conformal Prediction.
abstract: Poly(ADP-ribose) polymerases (PARPs) play a key role in DNA damage repair. PARP inhibitors act as chemo- and radio- sensitizers and thus potentiate the cytotoxicity of DNA damaging agents. Although PARP inhibitors are currently investigated as chemotherapeutic agents, their cross-reactivity with other members of the PARP family remains unclear. Here, we apply Proteochemometric Modelling (PCM) to model the activity of 181 compounds on 12 human PARPs. We demonstrate that PCM (R0 (2) test =0.65-0.69; RMSEtest =0.95-1.01 °C) displays higher performance on the test set (interpolation) than Family QSAR and Family QSAM (Tukey's HSD, α 0.05), and outperforms Inductive Transfer knowledge among targets (Tukey's HSD, α 0.05). We benchmark the predictive signal of 8 amino acid and 11 full-protein sequence descriptors, obtaining that all of them (except for SOCN) perform at the same level of statistical significance (Tukey's HSD, α 0.05). The extrapolation power of PCM to new compounds (RMSE=1.02±0.80 °C) and targets (RMSE=1.03±0.50 °C) is comparable to interpolation, although the extrapolation ability is not uniform across the chemical and the target space. For this reason, we also provide confidence intervals calculated with conformal prediction. In addition, we present the R package conformal, which permits the calculation of confidence intervals for regression and classification caret models.
authors.affiliation: Institut Pasteur, Unité de Bioinformatique Structurale, CNRS UMR 3825, Département de Biologie, Structurale et Chimie, 25, rue du Dr Roux, 75015, Paris, France. isidro.cortes@pasteur.fr.
authors.forename: Isidro
authors.initials: I
authors.lastname: Cortés-Ciriano
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Institut Pasteur, Unité de Bioinformatique Structurale, CNRS UMR 3825, Département de Biologie, Structurale et Chimie, 25, rue du Dr Roux, 75015, Paris, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Malliavin
mesh_terms: D006801:Humans; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry* / Q000235:genetics; D020539:Sequence Analysis, Protein
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases
keywords: Chemogenomics; PARP; Proteochemometrics; QSAR; Selectivity