A Topological and Spatial Analysis of FDA-Approved Drugs, Blood-Brain Barrier Permeants, Natural Products, and...

In this study, we present a comprehensive structural analysis of four distinct chemical libraries: FDA-approved drugs, blood-brain barrier (BBB) permeable agents, natural products (UNPDA), and human metabolites. Our multidimensional profiling reveals fundamental divergences in molecular architecture. While synthetic drugs (FDA) and CNS-active agents (BBB) follow continuous, Gaussian-like distributions for carbon hybridization, natural products exhibit biosynthetic quantization, discrete, high-intensity abundance spikes at C19 and C30, corresponding to steroid and triterpene scaffolds. Stereochemical analysis identifies a chirality-structure lock in natural products, where stereoisomer density peaks significantly at these same integers (Avg. 3.53 isomers/mol), a complexity feature absent in the diffuse distribution of synthetic libraries. Topologically, we identify hyper-globularity as a distinct signature for CNS permeability. Radial distribution function (RDF) analysis demonstrates that BBB agents possess a highly compressed aliphatic core, packing 93.2% of their sp³ mass within a 3 Å radius, compared to 84.4% for general FDA therapeutics. Furthermore, elemental profiling reveals a heteroatom gap: synthetic drugs exhibit a high electronegative atom-to-carbon ratio (0.43), whereas BBB agents (0.33) converge with the lipophilic profile of natural products (0.32), suggesting that CNS penetration requires a biomimetic reduction in polarity. These findings establish new quantitative metrics for designing neuro-compatible and biomimetic pharmacophores.