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Machine learning assisted design of highly active peptides for drug discovery.

Giguère S, Laviolette F, Marchand M, Tremblay D, Moineau S, Liang X, Biron É, Corbeil J - PLoS Comput. Biol. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science and Software Engineering, Université Laval, Québec, Canada.

ABSTRACT
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. Source code freely available at http://graal.ift.ulaval.ca/peptide-design/.

No MeSH data available.


Iterative process for the design of peptide ligands.
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pcbi.1004074.g002: Iterative process for the design of peptide ligands.

Mentions: We propose an iterative process that makes use of the proposed algorithms to accelerate the discovery of bioactive peptides. The procedure is illustrated in Fig. 2. First, an initial set of random peptides is synthesized, typically using a split and pool approach. The peptides are assayed in laboratory to measure their bioactivities. At this point, most peptides are poor candidates. They are then used as a training set to produce a predictor hy. Next, hy is used for the generation of K bioactive peptides by finding the K-longest paths in Ghy as described previously. A protocol P is constructed from these K bioactive peptides to assist the next round of combinatorial chemistry. Then, the algorithm described in the previous section is used to predict statistics on the protocol P. This ensures that the protocol meets expectations in terms of quality (average predicted bioactivity) and diversity (predicted bioactivity variance). To lower costs, one should proceed to synthesize and test the library only if expectations are met. This process can be repeated until the desired bioactivity is achieved.


Machine learning assisted design of highly active peptides for drug discovery.

Giguère S, Laviolette F, Marchand M, Tremblay D, Moineau S, Liang X, Biron É, Corbeil J - PLoS Comput. Biol. (2015)

Iterative process for the design of peptide ligands.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4388847&req=5

pcbi.1004074.g002: Iterative process for the design of peptide ligands.
Mentions: We propose an iterative process that makes use of the proposed algorithms to accelerate the discovery of bioactive peptides. The procedure is illustrated in Fig. 2. First, an initial set of random peptides is synthesized, typically using a split and pool approach. The peptides are assayed in laboratory to measure their bioactivities. At this point, most peptides are poor candidates. They are then used as a training set to produce a predictor hy. Next, hy is used for the generation of K bioactive peptides by finding the K-longest paths in Ghy as described previously. A protocol P is constructed from these K bioactive peptides to assist the next round of combinatorial chemistry. Then, the algorithm described in the previous section is used to predict statistics on the protocol P. This ensures that the protocol meets expectations in terms of quality (average predicted bioactivity) and diversity (predicted bioactivity variance). To lower costs, one should proceed to synthesize and test the library only if expectations are met. This process can be repeated until the desired bioactivity is achieved.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science and Software Engineering, Université Laval, Québec, Canada.

ABSTRACT
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. Source code freely available at http://graal.ift.ulaval.ca/peptide-design/.

No MeSH data available.