PMID- 25705261
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150223
LR  - 20220318
IS  - 1758-2946 (Print)
IS  - 1758-2946 (Electronic)
IS  - 1758-2946 (Linking)
VI  - 7
DP  - 2015
TI  - Prediction of the potency of mammalian cyclooxygenase inhibitors with ensemble 
      proteochemometric modeling.
PG  - 1
LID - 10.1186/s13321-014-0049-z [doi]
LID - 1
AB  - Cyclooxygenases (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 ([Formula: see text], and RMSEtest = 0.71) 
      outperformed models exclusively trained on compound ([Formula: see text], and 
      RMSEtest = 1.09) or protein descriptors ([Formula: see text] and RMSEtest = 1.10) 
      on the test set. Moreover, PCM predicted COX potency for 1,086 selective and 
      non-selective COX inhibitors with [Formula: see text] and RMSEtest = 0.76. These 
      values are in agreement with the maximum and minimum achievable [Formula: see 
      text] and RMSEtest values of approximately 0.68 for both metrics. Confidence 
      intervals for individual predictions were calculated from the standard deviation 
      of the predictions from the individual models composing the ensembles. Finally, 
      two substructure analysis pipelines singled out chemical substructures implicated 
      in both potency and selectivity in agreement with the literature. Graphical 
      AbstractPrediction of uncorrelated bioactivity profiles for mammalian COX 
      inhibitors with Ensemble Proteochemometric Modeling.
FAU - Cortes-Ciriano, Isidro
AU  - Cortes-Ciriano I
AD  - Departement de Biologie Structurale et Chimie, Institut Pasteur, Unite de 
      Bioinformatique Structurale; CNRS UMR 3825, 25, rue du Dr Roux, Paris, 75015 
      France.
FAU - Murrell, Daniel S
AU  - Murrell DS
AD  - Centre for Molecular Science Informatics, Department of Chemistry, University of 
      Cambridge, Cambridge, UK.
FAU - van Westen, Gerard Jp
AU  - van Westen GJ
AD  - European Molecular Biology Laboratory European Bioinformatics Institute Wellcome 
      Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
FAU - Bender, Andreas
AU  - Bender A
AD  - Centre for Molecular Science Informatics, Department of Chemistry, University of 
      Cambridge, Cambridge, UK.
FAU - Malliavin, Therese E
AU  - Malliavin TE
AD  - Departement de Biologie Structurale et Chimie, Institut Pasteur, Unite de 
      Bioinformatique Structurale; CNRS UMR 3825, 25, rue du Dr Roux, Paris, 75015 
      France.
LA  - eng
PT  - Journal Article
DEP - 20150116
PL  - England
TA  - J Cheminform
JT  - Journal of cheminformatics
JID - 101516718
PMC - PMC4335128
OTO - NOTNLM
OT  - Applicability domain
OT  - Chemogenomics
OT  - Cyclooxygenases
OT  - Ensemble modeling
OT  - Proteochemometrics
OT  - QSAR
EDAT- 2015/02/24 06:00
MHDA- 2015/02/24 06:01
PMCR- 2015/01/16
CRDT- 2015/02/24 06:00
PHST- 2014/08/01 00:00 [received]
PHST- 2014/11/21 00:00 [accepted]
PHST- 2015/02/24 06:00 [entrez]
PHST- 2015/02/24 06:00 [pubmed]
PHST- 2015/02/24 06:01 [medline]
PHST- 2015/01/16 00:00 [pmc-release]
AID - 49 [pii]
AID - 10.1186/s13321-014-0049-z [doi]
PST - epublish
SO  - J Cheminform. 2015 Jan 16;7:1. doi: 10.1186/s13321-014-0049-z. eCollection 2015.