Predicting Biological Functions of Compounds Based on Chemical-Chemical Interactions

Hu, Le-Le; Chen, Chen; Huang, Tao; Cai, Yu-Dong; Chou, Kuo-Chen

Predicted results for the compounds with unknown metabolic pathway Encouraged by the quite promising results obtained by the 5fold cross-validation test on the benchmark dataset of the 3,137 compounds, we applied the method to the 5,549 compounds whose metabolic pathways are unknown as mentioned in the Materials and Methods section. The predicted results thus obtained are given in Table S1 . As discussed above, we selected the metabolic pathway classes obtained by the 1 st and 2 nd order predictions for these compounds, in hoping that the information thus obtained may provide useful clues for further investigations. Actually, it is interesting to see that many of our predicted results have proved to be reasonable according to the reports from other investigators. For example, N-acetylgalactosamine 4-sulfate and its interactive compounds with pathway information are shown in Table 4 . N-acetylgalactosamine 4-sulfate can bind to sulfate, glucuronic acid, galactose, xylose, fucose, Na(+), glycerol, and phosphate to form complex to perform the biological function [39] . In PubMed Abstracts, N-acetylgalactosamine 4-sulfate is comentioned with sulfate [40] , glucuronic acid [41] , galactose [42] , 39-phospho.pho. [43] , sugar-1-phosph. [44] , UDP-GlcNAc [45] , indole-3-glyce. [46] , N-acetyl-D-glucosamine [47] , and GDPmannose [44] . Besides, N-acetylgalactosamine 4-sulfate and Nacetyl-D-glucosamine share a similar structure and the difference is that N-acetylgalactosamine 4-sulfate has a sulfate at the position 4 of the ring while N-acetyl-D-glucosamine has not [38] . From these evidences, N-acetylgalactosamine 4-sulfate is supposed to participate in the same metabolic pathways as its interactive compounds. It can be seen from Table 4 that most of the interactive compounds of N-acetylgalactosamine 4-sulfate belong to the 1 st and 2 nd metabolic pathway classes. By considering all the interactions and the interaction confidence scores, it was predicted that Carbohydrate Metabolism (the 1 st class) and Energy Metabolism (the 2 nd class) would be the possible metabolic pathway classes that N-acetylgalactosamine 4-sulfate belongs to. Actually, as a carbohydrate, N-acetylgalactosamine 4-sulfate reacts with Chondroitin 4-sulfate to form hydrogen oxide and G12336 (i.e. (GalNAc) 2 (GlcA) 1 (S) 2 ), one kind of glycan which can participate in Carbohydrate and Energy Metabolism. Therefore, N-acetylgalactosamine 4-sulfate may also participate in Carbohydrate and Energy Metabolism. Another example is that cyclopropylamine in Table 4 has 23 interactive compounds with known pathway information. Cyclopropylamine, cyanuric acid, ammonia, N-cyclopropylammelide, c0761, hydroxyl radicals are in the same pathway -N-cyclopropylmelamine degradation [48, 49] , where N-cyclopropylmelamine first reacts with hydrogen oxide to form N-cyclopropylammeline and ammonia, and then N-cyclopropylammeline also reacts with hydrogen oxide to form Ncyclopropylammelide and ammonia. After that, N-cyclopropylammelide reacts with hydrogen oxide to form cyanuric acid, cyclopropylamine and hydroxyl radicals. Finally, cyanuric acid is transformed into hydrogen oxide and ammonia through cyanurate degradation. Cyanuric acid, N-cyclopropylammelide, and c0761 are all in the 11 th pathway class. Therefore, cyclopropylamine may also belong to the 11 th pathway class (Xenobiotics Biodegradation and Metabolism). For other interactive compounds, they are comentioned with cyclopropylamine in PubM