A Quantitative Ring Complexity Index for Profiling Ring Topology and Chemical Diversity

The primary challenge in molecular design and drug discovery lies in efficiently exploring an immense chemical space (estimated between 1023 and 1060). The molecular scaffold serves as the core framework in medicinal chemistry, guiding diversity assessment, conformational studies, and scaffold hopping. While approximately 70% of approved drugs are based on known scaffolds, 98.6% of ring-based scaffolds in virtual libraries remain unvalidated. Traditionally, the complexity of ring systems, a crucial component of molecular scaffolds, has been assessed using the ring complexity index (RCI). However, RCI relies solely on the number of ring atoms, limiting its applicability. To address this, we propose the novel quantitative ring complexity index (QRCI), integrating ring diversity, topological complexity, and macrocyclic properties into a comprehensive complexity metric. QRCI can be computed without 3D conformational data and correlates strongly with synthetic accessibility and topological complexity, making it a valuable tool for evaluating ring system complexity, cheminformatics, scaffold optimization, and compound screening.