Linear discriminant analysis for skin sensitisation potential of diverse organic chemicals

Abstract

Skin sensitisation is one of the emerging toxicological endpoints posing a significant concern for human health. Stimulation index (SI) and murine local lymph node assay (LLNA) are used to estimate quantitatively the skin sensitisation potential to classify chemicals as skin sensitising or non-skin sensitising. To obviate these time-consuming and expensive approaches, development of in silico predictive models has gained considerable attention over the last few decades. In this background, we have developed a linear discriminant analysis (LDA) model for LLNA based on the skin sensitisation potential of 147 chemicals with wide diversity of molecular structures. The developed LDA model is rigorously validated using various classification metrics, which show that the model is able to discriminate the skin-sensitising and non-skin-sensitising compounds. The developed model and contribution plot suggested that rotatable bond or molecular flexibility gives negative contribution, whereas dragon branching index gives positive contribution towards both skin-sensitising and non-skin-sensitising compounds. The descriptors such as number of sulphonate fragments (thio-/dithio-), number of triple bonds, number of nitrogen atoms and quadric index have equal contributions on the skin-sensitising and non-skin-sensitising property. Finally, the model was applied to screen DrugBank database compounds to identify the compounds that are likely to have skin sensitisation.

Keywords:

• quantitative structure–activity relationship
• registration, evaluation and authorisation of chemicals
• organisation for economic co-operation and development
• linear discriminant analysis
• murine local lymph node assay

Acknowledgements

This research was funded by a major research project (KR) of Council of Scientific and Industrial Research, New Delhi. The authors thank the Department of Science and Technology (DST), Government of India, for awarding a Research fellowship under the INSPIRE scheme to SK. Ministry of Human Resources and Development, New Delhi, is thanked for a scholarship to AN.

Notes

^1. European Commission, Directive 2006/121/EC of the European Parliament and of the Council of 18 December 2006 amending Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances in order to adapt it to Regulation (EC) No 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) and establishing a European Chemicals Agency, Off. J. Eur. Union (2006), L 396/850 of 30.12.2006, Office for Official Publications of the European Communities (OPOCE), Luxembourg.

^2. EUCLIDEAN (a program written in C++) is developed and validated on known data-sets by Pravin Ambure (Email: [email protected]) of Drug Theoretics and Cheminformatics Laboratory, Jadavpur University.