Multi-task generative topographic mapping in virtual screening

• Published in: Journal of computer-aided molecular design 2019-03, Vol.33 (3), p.331-343
• Main Authors: Lin, Arkadii, Horvath, Dragos, Marcou, Gilles, Beck, Bernd, Varnek, Alexandre
• Format: Article
• Language: English
• Subjects: Animal Anatomy; Chemical Sciences; Cheminformatics; Chemistry; Chemistry and Materials Science; Coloring; Computer Applications in Chemistry; Computer simulation; Databases, Protein; Histology; Ligands; Manifolds; Mathematical models; Models, Molecular; Morphology; Neural networks; Neural Networks, Computer; Organic chemistry; Parameters; Physical Chemistry; Prediction models; Protein Binding; Protein Conformation; Proteins - chemistry; Screening; Structure-Activity Relationship; Topographic mapping; Topographic maps; Topography
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-019-00188-x

The previously reported procedure to generate “universal” Generative Topographic Maps (GTMs) of the drug-like chemical space is in practice a multi-task learning process, in which both operational GTM parameters (example: map grid size) and hyperparameters (key example: the molecular descriptor space to be used) are being chosen by an evolutionary process in order to fit/select “universal” GTM manifolds. After selection (a one-time task aimed at optimizing the compromise in terms of neighborhood behavior compliance, over a large pool of various biological targets), for any further use the manifolds are ready to provide “fit-free” predictive models. Using any structure–activity set—irrespectively whether the associated target served at map fitting stage or not—the generation or “coloring” a property landscape enables predicting the property for any external molecule, with zero additional fitable parameters involved. While previous works have signaled the excellent behavior of such models in aggressive three-fold cross-validation assessments of their predictive power, the present work wished to explore their behavior in Virtual Screening (VS), here simulated on hand of external DUD ligand and decoy series that are fully disjoint from the ChEMBL-extracted landscape coloring sets. Beyond the rather robust results of the universal GTM manifolds in this challenge, it could be shown that the descriptor spaces selected by the evolutionary multi-task learner were intrinsically able to serve as an excellent support for many other VS procedures, starting from parameter-free similarity searching, to local (target-specific) GTM models, to parameter-rich, nonlinear Random Forest and Neural Network approaches.