TpsA

TPSA, or Topological Polar Surface Area, is a molecular descriptor used in medicinal chemistry and cheminformatics to estimate a compound’s ability to cross biological membranes. It is calculated from a two-dimensional structure by summing the polar surface contributions of heteroatoms, typically nitrogen, oxygen, and sometimes sulfur, expressed in square angstroms (Å^2).

The method most widely used was introduced by Ertl, Rohde, and Selzer in 2000 and assigns fixed fragment constants to polar atoms to obtain a fast, topology-based estimate without requiring three-dimensional geometry. Many software tools implement TPSA, including RDKit, Open Babel, and various commercial chemoinformatics packages.

TPSA is commonly used to predict aspects of pharmacokinetics, including oral bioavailability, intestinal absorption, and blood–brain barrier penetration. Lower TPSA generally correlates with higher membrane permeability, while higher TPSA can improve aqueous solubility but reduce permeability. In development, thresholds from Lipinski’s Rule of Five and Veber’s rules are often cited: TPSA under about 140 Å^2 is associated with good oral bioavailability, and values under about 90 Å^2 can favor CNS penetration when combined with other factors.

TPSA has limitations. It is computed from a 2D representation and does not capture conformational effects, intramolecular hydrogen bonding, or protonation states at physiological pH. Consequently, TPSA is an approximate predictor and should be considered alongside other descriptors such as logP, molecular weight, hydrogen-bond donors and acceptors, and experimental data.

In practice, TPSA remains a widely used, simple descriptor in early-stage screening and property estimation, helping researchers prioritize compounds for further optimization.