Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties

• Published in: Journal of medicinal chemistry Vol. 43; no. 20; pp. 3714 - 3717
• Main Authors: Ertl, Peter, Rohde, Bernhard, Selzer, Paul
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05.10.2000
• Subjects: Biological and medical sciences; Biological Availability; Biological Transport; General pharmacology; Medical sciences; Models, Molecular; Molecular Structure; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Reproducibility of Results; Gut; Prediction; Biomembrane; Blood brain barrier; Modeling; Absorption; Penetration; Structure activity relation; Drug library; Molecular model; Surface properties; Surface area; Pharmacokinetics; Polar molecule
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000942e

Molecular polar surface area (PSA), i.e., surface belonging to polar atoms, is a descriptor that was shown to correlate well with passive molecular transport through membranes and, therefore, allows prediction of transport properties of drugs. The calculation of PSA, however, is rather time-consuming because of the necessity to generate a reasonable 3D molecular geometry and the calculation of the surface itself. A new approach for the calculation of the PSA is presented here, based on the summation of tabulated surface contributions of polar fragments. The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA (the correlation coefficient between 3D PSA and fragment-based TPSA for 34 810 molecules from the World Drug Index is 0.99), while the computation speed is 2−3 orders of magnitude faster. The new methodology may, therefore, be used for fast bioavailability screening of virtual libraries having millions of molecules. This article describes the new methodology and shows the results of validation studies based on sets of published absorption data, including intestinal absorption, Caco-2 monolayer penetration, and blood−brain barrier penetration.