Editing ChargeCalculator:Case studies (section)

=Paracetamol – atomic charges and chemical reactivity in small drug like molecules=

[[File:Paracetamol.png|thumb|right|650px|The most positive H in the paracetamol molecule correspond to the most reactive sites during the metabolic degradation of paracetamol.]]

N-acetyl-p-aminophenol, commonly known as paracetamol, is a widely used analgesic and antipyretic. Its mechanism of action is believed to be the inhibition of the protein cyclooxygenase 2, regulating the production of pro-inflammatory compounds. The metabolic break down of paracetamol has been the subject of intense study, since it holds the key to both its therapeutic action and toxicity. 

We calculated atomic charges in paracetamol using ACC. The geometry of the paracetamol molecule corresponded to the ideal coordinates for the entry TYL from the wwPDB Chemical Compounds Database (wwPDB CCD: TYL). The default ACC settings were used. The computation took less than 1s, and the complete results are available on the [http://ncbr.muni.cz/ACC/CaseStudy/Paracetamol ACC web page]. 

A quick analysis reveals that the phenolic H (position HO4) is the most acidic proton (highest positive charge) in the molecule, suggesting a faster and easier dissociation of this O-H bond. Indeed up to 90% of metabolic degradation happens at position HO4 (glucunronidationration, sulphonation). Additionally, up to 15% of metabolic degradation involves dehydrogenation oxidation at the phenolic (HO4) and amidic positions (HN), the two most positive H in the paracetamol molecule. While paracetamol is a very small molecule with few polar sites, the same principle can be applied in reasoning out highly reactive sites in more complex molecules. 
 
You can try out this particular computation setup [http://webchem.ncbr.muni.cz/Platform/ChargeCalculator/Result/8ed40f3c-48e7-4a1d-9d86-7ec541c95984?example=Paracetamol here], and make sure to use the interactive guides for additional explanations. We have used the default ACC settings, meaning that the total charge was 0, the EEM parameter set covers NPA atomic charges at the B3LYP/6-31G* level of theory. These charges are expected to support qualitative chemical concepts like induction and conjugation. In general, it is a good idea to try several charge definitions. One or more of these might prove useful in further modeling studies. If you plan to run molecular dynamics, it is good to use charges which are compatible with the particular force field you plan to use. For instance, if the force field is known to use atomic charges based on electrostatic potential mapping, pick at least one EEM parameter set developed with this charge definition.
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