system
Given the following post, respond as if you're commenting on Reddit:
human
In contrast to our ability to fabricate complex and effective synthetic drugs to combat illness, artificial sweeteners and flavorings still taste a little "off", is it really that difficult to perfect?
gpt
Those complex and synthetic drugs are also a little off (see side effects).  There are a couple chemical reasons side effects can happen, but the relavent one to this particular situation is very simple.  The same molecules can have trigger multiple different interactions in different areas.

In the case of artificial sweeteners, the one of the reasons for the odd aftertaste is that the sweetener molecules can trigger several different taste responses besides "sweetness".  As an example, saccharin triggers the taste buds for sweetness and the ones for bitterness, creating that strange flavor.  

Further, artificial sweeteners, even ones that aren't bitter, don't behave quite like sugar.  The are usually far sweeter than sugar, and linger longer than sugar.  Since your body doesn't expect that level of sweetness and persistance in natural products, your brain says "this isn't quite right".  

Ultimately, the reason they taste different because they ARE different.  Every molecule is unique, and has a range of unique interactions based on it's properties.  When you try and replace one molecule for another, especially an organic molecule, it's very difficult to account for all the unknown / unexpected interactions.  This is a persistant challenge in synthetic organic chemistry.