polar surface area

{{more footnotes needed|date=December 2017}}Image:Paracetamol Electron Map.png showing polar areas in red and blue]]

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.

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.{{cite journal | vauthors = Pajouhesh H, Lenz GR | title = Medicinal Chemical Properties of Successful Central Nervous System Drugs. | journal = NeuroRx | volume = 2 | issue = 4 | pages = 541–553 |date=Oct 2005 | doi = 10.1602/neurorx.2.4.541 | pmid=16489364 | pmc=1201314}} 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.{{cite journal | vauthors = Hitchcock SA, Pennington LD | title = Structure - Brain Exposure Relationships | journal = J. Med. Chem. | volume = 49 | issue = 26 | pages = 7559–7583 |date=May 2006 | doi = 10.1021/jm060642i | pmid = 17181137 }}

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{{Cite journal |last=Shityakov |first=Sergey |last2=Neuhaus |first2=Winfried |last3=Dandekar |first3=Thomas |last4=Förster |first4=Carola |date=2013 |title=Analysing molecular polar surface descriptors to predict blood-brain barrier permeation |url=https://pubmed.ncbi.nlm.nih.gov/23428480/ |journal=International Journal of Computational Biology and Drug Design |volume=6 |issue=1-2 |pages=146–156 |doi=10.1504/IJCBDD.2013.052195 |issn=1756-0756 |pmid=23428480}}., 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{{Cite journal |last=Hester |first=Gabrielle |last2=Lang |first2=Tom |last3=Madsen |first3=Laura |last4=Tambyraja |first4=Rabindra |last5=Zenker |first5=Paul |date=January 2019 |title=Timely Data for Targeted Quality Improvement Interventions: Use of a Visual Analytics Dashboard for Bronchiolitis |url=https://pubmed.ncbi.nlm.nih.gov/30841007/ |journal=Applied Clinical Informatics |volume=10 |issue=1 |pages=168–174 |doi=10.1055/s-0039-1679868 |issn=1869-0327 |pmc=6402943 |pmid=30841007}} 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.{{Cite web |title=Δραστική: PARACETAMOL |url=https://farmako.net/el/drastikes/drastiki?SearchTerm=PARACETAMOL |access-date=2024-04-10 |website=farmako.net |language=en}}