Computational design of new molecular scaffolds for medicinal chemistry, part II: Generalization of analog series-based scaffolds

Abstract

Aim: Extending and generalizing the computational concept of analog series-based (ASB) scaffolds. Materials & methods: Methodological modifications were introduced to further increase the coverage of analog series (ASs) and compounds by ASB scaffolds. From bioactive compounds, ASs were systematically extracted and second-generation ASB scaffolds isolated. Results: More than 20,000 second-generation ASB scaffolds with single or multiple substitution sites were extracted from active compounds, achieving more than 90% coverage of ASs. Conclusion: Generalization of the ASB scaffold approach has yielded a large knowledge base of scaffold-capturing compound series and target information. Lay abstract: 'Scaffolds' represent core structures of small molecules. A series of structural analogs contains the same scaffold (core) and different functional groups attached to the core. Scaffolds are often used to organize active compounds into different structural families. They are also used to aid in compound design in medicinal chemistry. Scaffolds can be extracted computationally from single molecules or, following a recently introduced method, from analog series. Herein, an extension of the series-based scaffold methodology is presented to further increase the number of informative scaffolds that can be obtained and represent as many analog series and compounds as possible. Graphical abstract: The concept of analog series-based scaffolds was further extended and taking multiple substitution sites into account. The figure shows an exemplary second-generation analog series-based scaffold.