Spacial Score─A Comprehensive Topological Indicator for Small-Molecule Complexity

Abstract

The fraction of sp3-hybridized carbons (Fsp3) and the fraction of stereogenic carbons (FCstereo) are two widely employed scores of molecular complexity with strong links to biologically relevant features. However, they do not comprehensively express molecular topology, and they often do not match the chemical intuition of complexity. We propose the spacial score (SPS) as an empirical scoring system that builds upon the principle underlying Fsp3 and FCstereo and expresses the spacial complexity of a compound in a uniform manner on a highly granular scale. The size-normalized SPS (nSPS) can differentiate distributions of natural products and synthetic compounds and is applicable in the analysis of biological activity data. Analysis of the ChEMBL database revealed general trends of increasing selectivity and potency with increasing nSPS. SPS can also be used advantageously in planning and analysis of synthesis programs for direct comparison of chemical transformations and intermediates in reaction sequences.