Toward Understanding the Cold, Hot, and Neutral Nature of Chinese Medicines Using in Silico Mode-of-Action Analysis

One important, however, poorly understood, concept of Traditional Chinese Medicine (TCM) is that of hot, cold, and neutral nature of its bioactive principles. To advance the field, in this study, we analyzed compound–nature pairs from TCM on a large scale (>23 000 structures) via chemical space visualizations to understand its physicochemical domain and in silico target prediction to understand differences related to their modes-of-action (MoA) against proteins. We found that overall TCM natures spread into different subclusters with specific molecular patterns, as opposed to forming coherent global groups. Compounds associated with cold nature had a lower clogP and contain more aliphatic rings than the other groups and were found to control detoxification, heat-clearing, heart development processes, and have sedative function, associated with “Mental and behavioural disorders” diseases. While compounds associated with hot nature were on average of lower molecular weight, have more aromatic ring systems t...