ToxinPred 3.0: An improved method for predicting the toxicity of peptides

Abstract Toxicity emerges as a prominent challenge in the design of therapeutic peptides, causing the failure of numerous peptides during clinical trials. In 2013, our group developed ToxinPred, a computational method that has been extensively adopted by the scientific community for predicting peptide toxicity. In this paper, we propose a refined variant of ToxinPred that showcases improved reliability and accuracy in predicting peptide toxicity. Initially, we used BLAST for alignment-based toxicity prediction, yet coverage was limited. We adopted a motif-based approach with MERCI software to identify unique toxic patterns. Despite specificity gains, sensitivity was compromised. We developed alignment-free methods using machine/deep learning, achieving a balance sensitivity and specificity of prediction. A deep learning model (ANN – LSTM with fixed sequence length) developed using one-hot encoding attained a 0.93 AUROC and 0.71 MCC on independent data. The machine learning model (extra tree) developed using compositional features of peptides achieved 0.95 AUROC and 0.78 MCC. Lastly, we developed hybrid or ensemble methods combining two or more models to enhance performance. Hybrid approaches, including motif-based and machine learning, achieved a 0.98 AUROC and 0.81 MCC. Evaluation on independent data demonstrated our method’s superiority. To cater to the needs of the scientific community, we have developed a standalone software, pip package and web-based server ToxinPred3 ( https://github.com/raghavagps/toxinpred3 and https://webs.iiitd.edu.in/raghava/toxinpred3/ ) . Author’s Biography Anand Singh Rathore is currently pursuing a Ph.D. in Computational Biology at the Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India. Akanksha Arora is currently pursuing a Ph.D. in Computational Biology at the Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India. Shubham Choudhury is currently pursuing a Ph.D. in Computational Biology at the Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India. Purava Tijare is a Project Fellow in Computational Biology at the Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India. Gajendra P. S. Raghava is currently working as a Professor and Head of the Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India. Highlights Implementation of alignment or similarly based techniques for predicting toxic peptides. Discovery of toxicity-associated patterns and identification of toxic regions in peptides. Development of machine and deep learning-based models for toxicity prediction. Ensemble methods that combine alignment-based and alignment-free methods. Web server and standalone software package for screening toxicity in peptides/proteins.