This work describes a novel approach based on advanced molecular similarity to predict the sweetness of chemicals. The proposed Quantitative Structure-Taste Relationship (QSTR) model is an expert system developed keeping in mind the five principles defined by the Organization for Economic Co-operation and Development (OECD) for the validation of (Q)SARs. The 649 sweet and non-sweet molecules were described by both conformation-independent extended-connectivity fingerprints (ECFPs) and molecular descriptors. In particular, the molecular similarity in the ECFPs space showed a clear association with molecular taste and it was exploited for model development. Molecules laying in the subspaces where the taste assignation was more difficult were modeled trough a consensus between linear and local approaches (Partial Least Squares-Discriminant Analysis and N-nearest-neighbor classifier). The expert system, which was thoroughly validated through a Monte Carlo procedure and an external set, gave satisfactory results in comparison with the state-of-the-art models. Moreover, the QSTR model can be leveraged into a greater understanding of the relationship between molecular structure and sweetness, and into the design of novel sweeteners.

• A chemical database called ChemTastesDB was created, which consists of 2944 organic and inorganic tastants. • Tastants have been curated and classified into 5 basic and 4 non-basic taste categories. • The chemical space of the ChemTastesDB has been analyzed with unsupervised machine learning. • ChemTastesDB is freely available on line and provides support for decision-making for designing new tastants.