A Topological and Spatial Analysis of FDA-Approved Drugs, Blood-Brain Barrier Permeants, Natural Products, and Metabolites.
VH, M., SA, A.H., MSA, Q., A, S., & MEA, Z. (2026). A Topological and Spatial Analysis of FDA-Approved Drugs, Blood-Brain Barrier Permeants, Natural Products, and Metabolites.. ChemMedChem. https://doi.org/10.1002/cmdc.70462
VH M, SA AH, MSA Q, A S, MEA Z. A Topological and Spatial Analysis of FDA-Approved Drugs, Blood-Brain Barrier Permeants, Natural Products, and Metabolites.. ChemMedChem. 2026; doi: 10.1002/cmdc.70462
VH M, SA AH, MSA Q, et al. A Topological and Spatial Analysis of FDA-Approved Drugs, Blood-Brain Barrier Permeants, Natural Products, and Metabolites.[J]. ChemMedChem. 2026. DOI: 10.1002/cmdc.70462.
@article{vh2026,
author = {Masand VH and Al-Hussain SA and Quadri MSA and Samad A and Zaki MEA},
title = {A Topological and Spatial Analysis of FDA-Approved Drugs, Blood-Brain Barrier Permeants, Natural Products, and Metabolites.},
journal = {ChemMedChem},
year = {2026},
doi = {10.1002/cmdc.70462},
note = {PMID: 42660644},
}
TY - JOUR AU - Masand VH AU - Al-Hussain SA AU - Quadri MSA AU - Samad A AU - Zaki MEA TI - A Topological and Spatial Analysis of FDA-Approved Drugs, Blood-Brain Barrier Permeants, Natural Products, and Metabolites. T2 - ChemMedChem PY - 2026 DO - 10.1002/cmdc.70462 AN - PMID:42660644 ER -
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.