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Small interfering RNAs (siRNAs) are largely modified with chemical molecules to enhance their properties for use in molecular biology research and therapeutic applications. Toxicity effects may arise due to these chemical moieties as well as sequence based off-targets at cellular level. Enormous resources are required to experimentally design and test the toxicity of these chemical modifications and their combinations on siRNAs. To address this problem, we developed TOXsiRNA web server to computationally predict the toxicity of chemically modified siRNAs and their off-targets. We selected 2749 siRNAs with different permutations and combinations of 21 different chemical modifications engineered on them. Next, we used Support Vector Machine (SVM), Linear Regression (LR), K-Nearest Neighbor (KNN) and Artificial Neural Network (ANN) machine learning applications to develop models. Best performance was displayed by mononucleotide composition based model developed with SVM, offering Pearson Correlation Coefficient (PCC) of 0.91 and 0.92 on training testing and independent validations respectively. Other sequence features like dinucleotide composition binary pattern and their combinations were also tested. Finally, three models of chemically modified siRNAs were implemented on the web server. Other algorithms that include predicting normal as well as chemically modified siRNA knockdown efficacy, off target etc. are also integrated. The resource is hosted online for scientific use freely at url: http://bioinfo.imtech.res.in/manojk/toxsirna.