Thursday, March 14, 2019

How important is small molecule structure determination for drug development and discovery?
Very. Let’s say you have a compound that does something amazing to your cell culture. You know the structure, and have a pretty good idea how it binds to its target receptor, and the pharmacological mechanism(s) responsible for its amazing effects. Before you can consider this lead compound a drug candidate, you have to consider a few things, including (but not limited to):
  • Solubility[1] - What kind of vehicle are you going to use to administer this compound? Good drug candidates are frequently poorly soluble in saline, but DMSO can be toxic.[2][3]
  • Bioavailability - When administered via injection will it distribute into tissues, or get stuck on plasma proteins and never make it out of the blood stream?
  • BBB permeability - Will it cross the blood-brain-barrier? Sometimes the answer you want is yes, sometimes it’s no.
  • Off-target interactions - What are the chances this compound might preferentially bind to say, potassium channels? That wouldn’t be good.
  • Metabolites - Might they be toxic? How about bioactive?
  • Route of administration - Turns out that humans don’t like getting shots.[4] People much prefer pills. Is the compound something that could be absorbed through the GI tract?
Anyway, good drug candidates frequently have structures designed to address these and other issues.

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