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

Peter Ertl,* Bernhard Rohde, and Paul Selzer
Cheminformatics, Novartis Pharma AG, WKL-490.4.35, CH-4002 Basel, Switzerland
J. Med. Chem., 2000, 43 (20), pp 3714–3717
DOI: 10.1021/jm000942e
Publication Date (Web): September 19, 2000
Copyright © 2000 American Chemical Society
*

 To whom correspondence should be addressed. Phone:  +41 61 69 67413. Fax:  +41 61 69 67416. E-mail:  peter.ertl@pharma.novartis.com.

Abstract

Abstract Image

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.

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History

  • Published In Issue October 05, 2000
  • Received July 17, 2000

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