Polar surface area

The polar surface area (PSA) or topological polar surface area (TPSA) of a molecule is defined as the surface sum over all polar atoms or molecules, primarily oxygen and nitrogen, also including their attached hydrogen atoms.

Electrical potential surface of paracetamol showing polar areas in red and blue

PSA is a commonly used medicinal chemistry metric for the optimization of a drug's ability to permeate cells. Molecules with a polar surface area of greater than 140 angstroms squared (Ų) tend to be poor at permeating cell membranes. For molecules to penetrate the blood–brain barrier (and thus act on receptors in the central nervous system), a PSA less than 90 Ų is usually needed.

TPSA is a valuable tool in drug discovery and development. By analyzing a drug candidate's TPSA, scientists can predict its potential for oral bioavailability and ability to reach target sites within the body. This prediction hinges on a drug's ability to permeate biological barriers.

Permeating these barriers, such as the Blood-Brain Barrier (BBB), the Placental Barrier (PB), and the Blood-Mammary Barrier (BM), is crucial for many drugs to reach their intended targets.

The BBB, for example, protects the brain from harmful substances. Drugs with a lower TPSA (generally below 90 Ų) tend to permeate the BBB more easily, allowing them to reach the brain and exert their therapeutic effects (Shityakov et al., 2013).

Similarly, for drugs intended to treat the fetus, a lower TPSA (below 60 Ų) is preferred to ensure they can pass through the placenta (Augustiño-Roubina et al., 2019).

Breastfeeding mothers also need consideration. Here, an optimal TPSA for a drug is around 60-80 Ų to allow it to reach the breast tissue for milk production, while drugs exceeding 90 Ų are less likely to permeate the Blood-Mammary Barrier.

See also

• Biopharmaceutics Classification System
• Cheminformatics
  • Chemistry Development Kit
  • JOELib
• Implicit solvation
• Lipinski's rule of five

Literature

• Pajouhesh, Hassan; Lenz, George R (2005). "Medicinal chemical properties of successful central nervous system drugs". NeuroRx. 2 (4): 541–553. doi:10.1602/neurorx.2.4.541. PMC 1201314. PMID 16489364.
• Clark, David E (1999). "Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption". Journal of Pharmaceutical Sciences. 88 (8): 807–14. doi:10.1021/js9804011. PMID 10430547.
• Palm, Katrin; Stenberg, Patric; Luthman, Kristina; Artursson1, Per (1997). "Polar molecular surface properties predict the intestinal absorption of drugs in humans". Pharmaceutical Research. 14 (5): 568–71. doi:10.1023/A:1012188625088. PMID 9165525. S2CID 7178582.{{cite journal}}: CS1 maint: numeric names: authors list (link)
• Ertl, Peter; Rohde, Bernhard; Selzer, Paul (2000). "Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties". Journal of Medicinal Chemistry. 43 (20): 3714–3717. doi:10.1021/jm000942e. PMID 11020286.
• Ertl, P. Polar Surface Area, in Molecular Drug Properties, R. Mannhold (ed), Wiley-VCH, pp. 111–126, 2007
• Shityakov, Sergey; Neuhaus, Winfried; Dandekar, Thomas; Förster, Carola (2013). "Analysing molecular polar surface descriptors to predict blood-brain barrier permeation". International Journal of Computational Biology and Drug Design. 6 (1–2): 146–56. doi:10.1504/IJCBDD.2013.052195. PMID 23428480.

External links

• Interactive Polar Surface Area calculator
• Free, Programmable TPSA Calculator