Machine learning assisted design of highly active peptides for drug discovery

The discovery of peptides possessing high biological activity is very challenging due to the enormous diversity for which only a minority have the desired properties. To lower cost and reduce the time to obtain promising peptides, machine learning approaches can greatly assist in the process and even partly replace expensive laboratory experiments by learning a predictor with existing data or with a smaller amount of data generation. Unfortunately, once the model is learned, selecting peptides having the greatest predicted bioactivity often requires a prohibitive amount of computational time. For this combinatorial problem, heuristics and stochastic optimization methods are not guaranteed to find adequate solutions. We focused on recent advances in kernel methods and machine learning to learn a predictive model with proven success. For this type of model, we propose an efficient algorithm based on graph theory, that is guaranteed to find the peptides for which the model predicts maximal bioactivity. We also present a second algorithm capable of sorting the peptides of maximal bioactivity. Extensive analyses demonstrate how these algorithms can be part of an iterative combinatorial chemistry procedure to speed up the discovery and the validation of peptide leads. Moreover, the proposed approach does not require the use of known ligands for the target protein since it can leverage recent multi-target machine learning predictors where ligands for similar targets can serve as initial training data. Finally, we validated the proposed approach in vitro with the discovery of new cationic antimicrobial peptides.Part of the complexity of drug discovery is the sheer chemical diversity to explore combined to all requirements a compound must meet to become a commercial drug. Hence, it makes sense to automate this chemical exploration endeavor in a wise, informed, and efficient fashion. Here, we focused on peptides as they have properties that make them excellent drug starting points. Machine learning techniques may replace expensive in-vitro laboratory experiments by learning an accurate model of it. However, computational models also suffer from the combinatorial explosion due to the enormous chemical diversity. Indeed, applying the model to every peptides would take an astronomical amount of computer time. Therefore, given a model, is it possible to determine, using reasonable computational time, the peptide that has the best properties and chance for success? This exact question is what motivated our work. We focused on recent advances in kernel methods and machine learning to learn a model that already had excellent results. We demonstrate that this class of model has mathematical properties that makes it possible to rapidly identify and sort the best peptides. Finally, in-vitro and in-silico results are provided to support and validate this theoretical discover