Spacial Score – A Comprehensive Topological Indicator for Small Molecule Complexity

Abstract

The fraction of sp3 hybridised carbons (Fsp3) and the fraction of stereogenic carbons (FCstereo) are two widely employed scores of molecular complexity with a strong link to biologically relevant features such as frequency, potency and selectivity of protein binding. However, due to their simplistic nature, 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 and on a highly granular scale for convenient ranking of and comparison between molecules. The size-normalised 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. Notably, SPS can also be used advantageously in planning and analysis of synthesis programs for direct comparison of chemical transformations and intermediates in reaction sequences, for instance in natural product total syntheses.