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

Abstract

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 sp 3 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.