musings on music and life

May 11, 2016

Review of DavidsonX D001x

Filed under: Chemistry, education — sankirnam @ 11:49 am

I recently completed the above course on EdX; the full title is:

DavidsonX: D001x Medicinal Chemistry: The Molecular Basis of Drug Discovery

I have taken biochemistry and medicinal chemistry/drug discovery courses several times in the past during my undergrad and graduate studies, but the quality and coverage of the topics in this course was far, far better than anything I had taken to date. Major kudos to Prof. Erland Stevens (the instructor) for doing a fantastic job. I highly recommend this course to anyone with an interest in medicinal chemistry or drug discovery (even if you’re not interested in doing it for a career).

The course starts from the basics and assumes a basic knowledge of organic chemistry and algebra/arithmetic. The organic background is required just so you know the basic rules of structural organic chemistry; there are no complex synthetic schemes or mechanisms in this course. As far as reactions are concerned, the only reactions really touched upon were those involved in oxidations by the liver.

The math required is tedious but not terribly overcomplicated; the majority of the questions involved calculations with Michaelis-Menten and Lineweaver-Burke plots, or using IC50 values and the Cheng-Prusoff equation. These can all be done with Excel or Google spreadsheets, and Prof. Stevens demonstrates clearly how to do it, but that still doesn’t reduce the tedium of going through the calculations. The main thing to watch out for when doing calculations is that the EdX system only gives you 1 or 2 opportunities to input the answer before closing it off, so you have to make doubly sure to check your math and make sure the answer is correct!

This was my first proper exposure to the concepts of ADME (Absorption, Distribution, Metabolism, Excretion), which is central to pharmaceutical science. Each of these concepts was covered in detail; for absorption, the main methods of delivery that were covered were the IV bolus and oral ingestion, although one should keep in mind that these are only 2 out of the many ways of getting a compound into the body (others include suppositories, inhalation, transdermal diffusion, etc.). Distribution covered the basic “one-compartment” and “two-compartment” models, different ways of thinking about how a compound gets around the body. In this case, the bloodstream can be thought of as a “compartment”, and the fatty tissues as another compartment, both with different volumes, and so the concentration of the compound in each will be different. The blood-brain barrier was not touched upon in this course; this is a topic of personal interest to me, and it can be thought of as a barrier that divides one of the compartments.

In the context of drug discovery, Prof. Stevens gave an overview of the major approaches used in the industry today, such as combinatorial chemistry, HTS, peptidomimetics, fragment-based and phenotype-based screening, and natural products. Functional group replacements and isosteres were also discussed, common ones being replacement of a -CH3 group by a -Cl and tetrazole for a carboxylic acid. As an organofluorine chemist, I know that it is common to use -F substitution in this regard, but this was not really touched upon. The lecture on SOSA (Selective Optimization of Side Activities) was a little confusing; Prof. Stevens used the classic example of the discovery of Viagra’s ability to treat erectile dysfunction to illustrate this, but I remember being misled by the associated questions. This could be improved in future iterations of the course.

The cool thing about the course was the Virtual Lab component, and this really brings to life the concepts taught in the course, allowing the students to see the challenges that medicinal chemists face. Using the “bioactivity predictor” feature of Molinspiration, one can input the structures of small organic compounds and conduct a rudimentary screen against some receptors, and further details can be interrogated with the admetSAR website. The challenge in these labs was to design molecules with an affinity for a certain receptor (as predicted by Molinspiration), but still having good ADME properties. This is really fun to play with, as it gives a sense to the interplay between organic structure and function (which is what structure-activity relationships (SARs) are all about).

This course is a great introduction to medicinal chemistry, and I highly recommend taking it in the future, if it is offered again. After this, one can dive into the medicinal chemistry literature (e.g. Journal of Medicinal Chemistry or BMCL) and gain a deeper understanding of the topics covered in the course and how they are actually being used right now.

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