Planning biosynthetic pathways of target molecules based on metabolic reaction prediction and AND-OR tree search

Bioretrosynthesis problem is to predict synthetic routes using substrates for given natural products (NPs). However, the huge number of metabolic reactions leads to a combinatorial explosion of searching space, which is high time-consuming and costly. Here, we propose a framework called BioRetro to predict bioretrosynthesis pathways using a one-step bioretrosynthesis network, termed HybridMLP combined with AND-OR tree heuristic search. The HybridMLP predicts precursors that will produce the target NPs, while the AND-OR tree generates the iterative multi-step biosynthetic pathways. The one-step bioretrosynthesis prediction experiments are conducted on MetaNetX dataset by using HybridMLP, which achieves 46.5%, 74.6%, 81.6% in terms of the top-1, top-5, top-10 accuracies. The great performance demonstrates the effectiveness of HybridMLP in one-step bioretrosynthesis. Besides, the evaluation of two benchmark datasets reveals that BioRetro can significantly improve the speed and success rate in predicting biosynthesis pathways. In addition, the BioRetro is further shown to find the synthetic pathway of compounds, such as ginsenoside F1 with the same substrates as reported but different enzymes, which may be the novel potential enzyme to have better catalytic performance.