Small molecule inhibitors and resistance

A great challenge in academic labs and pharmaceutical industries is the identification of small molecule inhibitors that could specifically target proteins involved in human diseases.
To do this, the most important step is the knowledge of biochemical features of the target protein. Human diseases associated to the target are usually well understood and the target has been previously validated: this means that its inhibition determines a recovery of normal cellular functionality.

X-ray crystallographic analysis and SAR (structure activity relationship) studies are crucial to identify and improve small molecules; otherwise, high throughput screening are performed, this route is usually followed by pharmaceutical or biotech companies that dispose of instrumentation to run the screening and manage data. Several small molecules identified as potential drug in one disease are tested in clinical studies in order to bypass resistance problems that could arise during long term treatment. Indeed, during this therapies a natural selection of mutations that provide the restoring of protein target activity, happens and makes useless the treatment.
Nevertheless, it’s necessary to continue research of small molecule inhibitor, especially in view of good results obtained, for instance, in tumoral diseases.