Quantitative Structural Thresholds for Blood–Brain Barrier Permeability Derived from Experimental logBB Measurements

Background/Objectives: Rules for predicting blood–brain barrier (BBB) permeability, including the CNS multiparameter optimization (CNS MPO) score, Lipinski’s Rule of Five, and Veber’s rules, were developed using relatively limited datasets and have not been systematically re-evaluated using modern large-scale experimental databases. Using the B3DB database, which contains 1058 experimentally measured logBB values, we derived quantitative, data-driven structural thresholds for BBB permeability and benchmarked them against established heuristic rules. Methods: Six key physicochemical properties were calculated for all compounds, and optimal classification thresholds were identified through exhaustive optimizations. Decision trees and scaffold analyses were used to generate interpretable medicinal chemistry guidelines. Results: The topological polar surface area (TPSA) emerged as the strongest single predictor of BBB permeability, with an optimal threshold of 66.8 Å2 (AUC = 0.731, 95% CI: 0.689–0.771). This threshold outperformed the approximated CNS MPO ≥ 4 (AUC = 0.625), Lipinski’s Rule of Five (AUC = 0.546), and Veber rules (AUC = 0.566). A simple two-parameter rule combining TPSA < 67 Å2 and H-bond donors ≤ 1 achieved 96.6% precision for BBB-permeable compounds while maintaining an AUC of 0.720. Decision tree analysis further confirmed TPSA as the dominant determinant of BBB permeability, whereas scaffold analysis identified the molecular frameworks associated with highly permeable and impermeable compounds. External validation provided preliminary support for the improved specificity of the proposed rule, compared with existing approaches. Conclusions: These findings suggest that the commonly applied TPSA threshold of 90 Å2 may be overly lenient. A data-driven threshold of approximately 67 Å2 substantially improved the discrimination of BBB permeability across the entire dataset. Compounds with TPSA values between 67 and 90 Å2 should be assessed on a case-by-case basis, considering the ionization state and active transport potential, rather than being automatically classified as BBB-permeable. These experimentally grounded rules offer a practical framework for the early-stage design of CNS leads.