Quantifying Functional-Group-like Structural Fragments in Molecules and Its Applications in Drug Design

A functional group in a molecule is a structural fragment consisting of a few atoms or a single atom that imparts reactivity to a molecule. Hence, defining functional groups is crucial in chemistry to predict the properties and reactivities of molecules. However, there is no established method in the literature for defining functional groups based on reactivity parameters. In this work, we addressed this issue by designing a set of predefined structural fragments along with reactivity parameters like electron conjugation and ring strain. This approach uses bond orders and atom connectivities to quantify the presence of these fragments within an organic molecule based on a given input molecular coordinate. To assess the effectiveness of this approach, we performed a case study to show the benefits of using these newly designed structural fragments instead of traditional fingerprint-based methods for grouping potential COX1/COX2 inhibitors by screening an approved drug library against aspirin molecule. The structural fragment-based model for ternary classification of rat oral LD₅₀ of chemicals showed performance similar to the fingerprint-based models. In evaluating the regression model performance for aqueous solubility, log(S), predictions, our approach outperformed the fingerprint-based model.