Computational Prediction of a New ADMET Endpoint for Small Molecules: Anticommensal Effect on Human Gut Microbiota.

The human gut microbiota (HGM), which are evolutionarily commensal in the human gastrointestinal system, are crucial to our health. However, HGM can be broadly shaped by multifaceted factors such as intake of drugs. About one-quarter of the existing drugs for humans, which are designed to target human cells rather than HGM, can notably alter the composition of HGM. Therefore, the anticommensal effect of human drugs should be avoided to the maximum extent possible in the drug discovery and development process. Nevertheless, the anticommensal effect of small molecules is a new ADMET (absorption, distribution, metabolism, excretion, and toxicity) end point, which was never predicted with the computational method before. In this work, we present the first machine-learning based consensus classification model with the accuracy (0.811 ± 0.012), precision (0.759 ± 0.032), specificity (0.901 ± 0.019), sensitivity (0.628 ± 0.036), F1-score (0.687 ± 0.023), and AUC (0.814 ± 0.030) respectively on the test set. Furthermore, we develop an easy-to-use "e-Commensal" program for the automatic prediction. Based on this program, virtual-screening of the food-constituent database (FooDB) indicates that 5888 of 23 202 food-relevant compounds are forecasted to possess an anticommensal effect on HGM. Several top-ranked anticommensal compounds in our prediction are further scrutinized and confirmed by experiments in the existing literature. To the best of our knowledge, this is the first classification model and stand-alone software for the prediction of commensal or anticommensal compounds impacting HGM.