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

Abstract

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.

A fully functional drug-eluting joint implant

“…We tested nine different antimicrobials (ciprofloxacin HCl, tobramycin, tetracycline HCl, gentamicin, vancomycin HCl, rifampin, teicoplanin, ceftriaxone, and fusidic acid) that spanned different polar surface areas (PSA, (72–663 Ȧ 2 )) and molecular volumes (MV, (282–1600 Ȧ 3 )) [30]. The ratio of these values (PSA/MV) was used to normalize polarity by molecular size.…”

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“…The delineation exists in a region of favorable properties for gastrointestinal absorption on a plot of two computed descriptors: ALOGP989 versus PSA 10. Because the region most populated by well‐absorbed molecules is elliptical, it was called the Egan egg .…”

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“…[a] Cells were treated with test compounds for 96 h. [b] Topological polar surface area 20. [c] The solid state of the test compounds was not characterized.…”