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Computational chemogenomics: Is it more than inductive transfer?

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Abstract

High-throughput assays challenge us to extract knowledge from multi-ligand, multi-target activity data. In QSAR, weights are statically fitted to each ligand descriptor with respect to a single endpoint or target. However, computational chemogenomics (CG) has demonstrated benefits of learning from entire grids of data at once, rather than building target-specific QSARs. A possible reason for this is the emergence of inductive knowledge transfer (IT) between targets, providing statistical robustness to the model, with no assumption about the structure of the targets. Relevant protein descriptors in CG should allow one to learn how to dynamically adjust ligand attribute weights with respect to protein structure. Hence, models built through explicit learning (EL) by including protein information, while benefitting from IT enhancement, should provide additional predictive capability, notably for protein deorphanization. This interplay between IT and EL in CG modeling is not sufficiently studied. While IT is likely to occur irrespective of the injected target information, it is not clear whether and when boosting due to EL may occur. EL is only possible if protein description is appropriate to the target set under investigation. The key issue here is the search for evidence of genuine EL exceeding expectations based on pure IT. We explore the problem in the context of Support Vector Regression, using more than 9,400 \(pK_i\) values of 31 GPCRs, where compound–protein interactions are represented by the concatenation of vectorial descriptions of compounds and proteins. This provides a unified framework to generate both IT-enhanced and potentially EL-enabled models, where the difference is toggled by supplied protein information. For EL-enabled models, protein information includes genuine protein descriptors such as typical sequence-based terms, but also the experimentally determined affinity cross-correlation fingerprints. These latter benchmark the expected behavior of a quasi-ideal descriptor capturing the actual functional protein-protein relatedness, and therefore thought to be the most likely to enable EL. EL- and IT-based methods were benchmarked alongside classical QSAR, with respect to cross-validation and deorphanization challenges. A rational method for projecting benchmarked methodologies into a strategy space is given, in the aims that the projection will provide directions for the types of molecule designs possible using a given methodology. While EL-enabled strategies outperform classical QSARs and favorably compare to similar published results, they are, in all respects evaluated herein, not strongly distinguished from IT-enhanced models. Moreover, EL-enabled strategies failed to prove superior in deorphanization challenges. Therefore, this paper raises caution that, contrary to common belief and intuitive expectation, the benefits of chemogenomics models over classical QSAR are quite possibly due less to the injection of protein-related information, and rather impacted more by the effect of inductive transfer, due to simultaneous learning from all of the modeled endpoints. These results show that the field of protein descriptor research needs further improvements to truly realize the expected benefit of EL.

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Abbreviations

CG:

Chemogenomics

GA:

Genetic algorithm

DS:

Descriptor space

GPCR:

G-protein coupled receptor

QSAR:

Quantitative structure–activity relationships

SVM:

Support vector machine

SVR:

Support vector regression

IT:

Inductive transfer

MTL:

Multi-task learning

RMSE:

Root mean squared error

ISIDA:

In silico design and data analysis

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Acknowledgments

The authors thank the High Performance Computing centers of the Universities of Strasbourg, France, and Cluj, Romania, for having hosted a part of the herein reported calculations. This work was also supported in part by a Grant-in-Aid for Young Scientists from the Japanese Society for the Promotion of Science [Kakenhi (B) 25870336]. Special thanks are given to Professor Jürgen Bajorath of the University of Bonn for extracting and cleaning the herein used datasets. This research was additionally supported by the Funding Program for Next Generation World-Leading Researchers as well as the CREST program of the Japan Science and Technology Agency. J. B. Brown and Yasushi Okuno are supported in part by grants from Chugai Pharmaceutical Co. Ltd. and Mitsui Knowledge Co. Ltd.

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Authors and Affiliations

  1. Laboratoire de Chémoinformatique, UMR 7140 CNRS, Univ. Strasbourg, 1, rue Blaise Pascal, 67000 , Strasbourg, France

    Gilles Marcou, Alexandre Varnek & Dragos Horvath

  2. Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan

    J. B. Brown & Yasushi Okuno

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  1. J. B. Brown
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Correspondence to Dragos Horvath.

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Brown, J.B., Okuno, Y., Marcou, G. et al. Computational chemogenomics: Is it more than inductive transfer?. J Comput Aided Mol Des 28, 597–618 (2014). https://doi.org/10.1007/s10822-014-9743-1

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