COVID-19: I. Chloroquine

2020 has been an unprecedented and disorienting year for everyone. To be honest, I had to look back through my notes to really put myself in pre-Covid frame of mind to make a reasonable transition for this update. What were the goals, concerns and hopes for the site back in February 2020? And after the refreshing from my search, I did remember that a recent objective the pathway search engine had accomplished was to independently discover a synthesis pathway for Daraprim (pyrimethamine). And as always, finding ways to improve the interface and make it more user friendly was a high priority. 

But when the world changed in mid-March, I decided that I would spend as much energy as I had for the site to see if I could possibly contribute to the fight against Covid-19. I knew that it might be a long shot, and of course any work here does not merit comparison with that of our front line and essential workers, but I did want to see if there is any part the site could play in helping the world solve the pandemic.

The first idea I came up with was to model one of the most promising drugs for treatment of Covid-19. In April, I considered modeling either Remdesivir or Chloroquine. Looking at the chemical structure of the two, I considered the modeling of Chloroquine far more feasible. In fact, some of the moieties of the Remdesivir structure I had not yet acquired the chemical knowledge to model or even properly name. And at the time, Hydroxychloroquine was legitimately being considered as an effective treatment.

The first step to implement support for Chloroquine was to look at the base fused ring component of the molecule. Fortunately, support in the interface was already in place for bicyclo[4.4.0]decane, so support only had to be added for the aromatic version of the fused ring, napthalene, and then afterwards the more specific version quinoline. Support for these two mainly involved updating the IUPAC naming engine. 

Next, support for tertiary amines needed to be added to handle the N,N-diethylpentan-2-yl side chain protruding from the amino group located at locant number 5 of the quinoline. This adjustment to the interface proved to be straight forward as well. I did make a mental note at the time that it would be MUCH more efficient to allow the user to select which carbon of an alkane chain addition they wished to attach to the current molecule; the process at the time of adding a pentan-2-yl side chain involved first attaching a butyl and then attaching a methyl to the head of the butyl. 

Finally, I took a look at the resulting chloroquine molecule and thought to myself hmm, this is getting pretty convoluted and messy. And as the site is also optimized to work on a small screen device, cleaning it up became even more of a priority. I decided to implement a mode by which the user could view the molecule in a line structure format: where carbons are represented by a point and other atoms by their chemical symbol. After this clean up optimization, the resulting chloroquine molecule is easier to view and interact with.

Standards: Existing IUPAC naming conventions were again followed in the modeling of chloroquine. Specifically, once the interface recognized that the bicyclo[4.4.0]decane skeleton was aromatic, it named it as napthalene. Furthermore, once it recognized a napthalene with a nitrogen heteroatom at the 1 locant, it named it quinoline. There was some trial and error involved to ensure proper stereochemistry naming resulted.

Numbering of locants for the napthalene and quinoline molecules follows the rules per Organic Nomenclature.

Controls: The "View Atom Abbreviation Mode" toggle was added to the control buttons. This allows the user to toggle between viewing full ball and stick molecule respresentations and line structure representations of the molecules. 

Future Considerations: As mentioned previously, implementing support for chloroquine made it clear that the interface would be much more effective if the user could select which carbon of an alkane chain would be attached to the existing molecule when adding a chain. This would allow the user to select the second carbon of pentane when wishing to add the radical pentan-2-yl.

AND as most of us with some knowledge of the life sciences are aware, unfortunately hydroxychloroquine proved to NOT be effective as a treament for COVID-19. Nevertheless, I took the enhancements of the interface and search engine provided from modeling chloroquine as valuable gains for the site, and turned my attention to the drug more promising at the time: Remdesivir.