# Derek Nexus Consultancy Report

CONFIDENTIAL

ForthTox Limited PO Box 13550, Linlithgow, West Lothian, EH49 7YU, U.K. Telephone +44 (0)1506-844036

www.forthtox.com
Page 1 of 8 

### Toxicological Analysis of using

Derek Nexus

Prepared for:

Date of report: 11 September 2012

ForthTox report ref : 

### CSI001drkCONFIDENTIAL ForthTox Report CSI001drk Page 2 of 8 

# The Derek Nexus System

The Derek Nexus system has been designed fo r the qualitative prediction of the possible toxicity of chemicals. The predictions made by Derek Nexus are intended as an aid to toxicological assessment and, where appropriate , should be used in conjunction with other methods. The absence of Derek Nexus pr edictions for any gi ven compound in no way implies that the compound is, or is expected to be, non-toxic.



# Disclaimer

Lhasa Limited make no warranties, expressed or implied, with re spect to Derek Nexus or the output thereof. In particular , but without limitation, Lhasa Limited make no representation or warranty of merchantability or of fitness for any specific purpose of use. In no event shall Lhasa Limited be liable for any consequential or incidental damages arising from or relating to, the use of Derek Nexus or the output thereof.

Lhasa Limited

22-23 Blenheim Terrace

Woodhouse Lane

Leeds LS2 9HD UK x Tel: +44 (0)113 394 6020 Fax: +44 (0)113 394 6099

E-mail: info@lhasalimited.org

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# Derek Nexus Consultancy Report

Toxicological Analysis of usmg Derek Nexus

Date of analysis: 16 th July 2012 Program version: Derek Nexus 2.0.3

ForthTox report ref: CSIOOI drk

Personnel responsible

Structure entry, 0 R Woolley PhD, BSc, MSB, CBiol processing and reporting European Registered Toxicologist

Report review A P A H Woolley MSc, DABT, FRCPath, ERT European Registered Toxicologist

This report has been generated from output from Derek Nexus 2.0.3, using the structure
illustrated and the processing constraints and endpoints described.



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### Introduction

was evaluate d for multiple toxicological endpoints in a range of mammalian and bacter ial species using Derek Nexus.

The following structures, copied from the Derek output, were processed:



### Protocol adopted for processing

Knowledge base version: 11_16_07_2012

Species: Escherichia coli

, Salmonella typhimurium , bacterium, dog, guinea pig, hamster, human, mammal, monkey, mouse, primate, rabbit, rat and rodent Endpoints searched: Carcinogenicity, Chromosome damage, Genotoxicity, HERG channel inhibition, Hepatotoxicity, Irritation, Miscellaneous endpoints, Mutagenicity, Ocular toxicity, Rapid prototypes: bladder disorders, Rapid prototypes: blood in urine, Rapid prototypes: bone marrow toxicity, Rapid prototypes: bradycardia, Rapid prototypes: chromosome damage in vitro, Rapid prototypes: hepatotoxicity, Rapid prototypes: kidney disorders, Rapid prototypes: mitochondrial dysfunction, Rapid prototypes: nephrotoxicity, Rapid prototypes: splenotoxicity,CONFIDENTIAL ForthTox Report CSI001drk Page 5 of 8 Rapid prototypes: thyroid toxicity, Reproductive toxicity, Respiratory sensitisation, Skin sensitisation, Thyroid toxicity Processing constraints: The option to perceive tautomers was selected.

Rapid prototype alerts are typi cally developed within the Derek knowledge base to describe

initial classes of structures associated with toxicological effects identified from a large dataset. They have a specific scope and limite d comments but do not c ontain references or examples. They are useful as an i ndication of a pote ntial toxicophore.



### Result

Nothing to report



### Comment and discussion

Derek Nexus assigns various leve ls of non-numeric likelihood to its predictions ranging from CERTAIN to CONTRADICTED, via PROBABLE, PLAUSIBLE, EQUIVOCAL, DOUBTED, IMPROBABLE, IMPOSSIBLE and OP EN. In the Derek lexicon, PLAUSIBLE

indicates that the structure has activated an alert for the endpoint in question. There is

sufficient information in the database to support the prediction. EQUIVOCAL – indicates that there is an equal weight of evidence fo r and against the proposition. OPEN – means that there is no evidence that suppor ts or opposes the proposition.

was evaluate d for multiple toxicological endpoints in a range of mammalian and bacterial species usi ng Derek Nexus. No alerts were triggered by this structure. Furthermore, it is likely that th e boron will not be available to cause toxicity as it is covalently bound to the oxygen molecules and thus is likely be sterically shielded and

hindered.

Derek Nexus has been accepted by regulatory ag encies such as the FDA and the EMEA for the prediction of the genotoxic ity of pharmaceutical impurities. The accuracy of Derek for Windows has been assessed in a number of publications.

Derek for Windows (DfW; the predecessor of De rek Nexus) is considered to be reliably predictive of mutagenicity, carci nogenicity and, to a lesser extent, genotoxicity (based in part

on the number of alerts for each in the soft ware) [Dearden (2003), Hu lzebos (2003) Hayashi

et al (2005) and Snyder et al (2004)].CONFIDENTIAL ForthTox Report CSI001drk Page 6 of 8 Hulzebos and Posthumus R (2003) reported th at DfW correctly categorised 90% of the chemicals in chemical classes, while 10% of th e structural fragments needed a more detailed description. The accuracy of prediction was ar ound 75% for genotoxicity and carcinogenicity

for a limited number of chemicals. Irritation an d reproductive toxicity were predicted poorly.

It should be noted that this review was conducted using an earlier version of DfW (version 5) and that considerable development of the software has taken place since then, in the form of annual updates.

Snyder assessed DfW 5 and two other commonly used computer databases, using information for 394 marketed pharmaceuticals with Ames Salmonella reversion assay and other genetic toxicology findings extracted from the 2000–2002 Physicians’Desk Reference . They reported that Derek for Windows gave the following results for the Ames test:

Sensitivity: 14/27 (51.9%) Specificity: 260/346 (75.1%) Concordance: 274/372 (73.6%)

To a certain extent, the results of such comp arisons are dependent on the database used for the validation comparisons.

Hillebrecht et al (2011) comparatively evaluated several in silico systems for Ames test mutagenicity prediction, including Derek and Leadscope. They used a database purchased from Leadscope, a set of chemicals taken fr om a recent publication by Hansen, purged of chemicals common to the Leadscope data, and a se t of chemicals from pr oprietary data held by Hoffmann-La Roche. The results from the Roch e data set were said to be skewed by the high ratio of negative to positive chemicals in th e data compared (6.78) to that for the other two sets (1.27 for Leadscope a nd 0.49 for the Hansen set). This work was based on the use of 9681 compounds of which a quarter were proprietary pharmaceutical compounds. Derek showed good sensitivity (approx imately 70%) and specificity (approximately 78% for the Leadscope database and 62% fo r the Hansen chemicals).

Negative predictions of mutagenicity by such so ftware have been accepted as indicating the

absence of a structural alert and that no fu rther toxicological in vestigation would be

necessary.

Using DfW (the predecessor of Derek Nexus) a review of a guinea pig archive data for compounds eliciting allergic c ontact dermatitis and a local lymph node assay (LLNA) data set was conducted. DfW correctly predicted 8 2.9% and 73% of the results from the guinea pig and LLNA data (Fedorowicz et al ., 2005).CONFIDENTIAL ForthTox Report CSI001drk Page 7 of 8 

### Conclusion

In conclusion, was evaluated for multiple toxicological endpoints in a range of mammalian and bacterial species using Derek Nexus. No alerts were triggered by this structure. Furthermore, it is likely that the boron wi ll not be available to cause toxicity as it is c ovalently bound to the oxygen molecu les and thus is likely be sterically shielded and hindered.CONFIDENTIAL ForthTox Report CSI001drk Page 8 of 8 References used by DEREK:

None.

References used by ForthTox:

Dearden, J.C. (2003). In silico prediction of drug toxicity. Journal of Computer-Aided Molecular Design 17,119–127.

Fedorowicz, A., Singh, H., Soderholm. S. & Demchuk, E. (2005) Structure-activity models

for contact sensitization. Chem Res Toxicol. 18(6). pp 954-69.

Hayashi, M., Kamata, E., Hirose, A., Takahashi, M., Morita, T. and Ema, M. (2005). In silico assessment of chemical mutagenesis in comp arison with results of Salmonella microsome assay on 909 chemicals. Mutation Research 588 129–135.

Hillebrecht A, Muster W, Brigo A, Kansy M, Weiser T and Singer T (2011). Comparative

evaluation of in silico systems for Ames test mutagenicity prediction: scope and limitations. Chemical Research in Toxicology 24, 843-54.

Hulzebos, E.M. and Posthumus, R. (2003): (Q)SARS: Gatekeepers against risk on chemicals? SAR and QSAR in Environmental Research , 14 (4), 285–316.

Snyder RD, Pearl GS, Mandakas G, Choy WN , Goodsaid F, Rosenblum IY. (2004) Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genot oxicity of pharmaceutical molecules. Environ Mol Mutagen . 43(3), 143-58.