So far, there are two well-liked ways to discover brand new drugs. The first involves using existing commercially available libraries of compounds along with testing them on cells or animals to find one that will has the required characteristics. This kind of hit-along with-miss approach is actually straightforward yet time-consuming, running anywhere coming from three months to two years to screen between 3,000 to 20,000 compounds.
The various other strategy is actually called “structure-based drug design.” With This kind of approach, you first need a high-resolution photograph of the receptor – showing the arrangement of every atom from the molecule. Then, using a computer program, you can examine up to 35 million molecules coming from a virtual chemical library called ZINC 15 to find a molecule that will will precisely interact – lock-along with-key style – with the receptor. that will is actually like having the precise dimensions of the International Space Station in order that will you can design a spacecraft that will can fits perfectly from the docking site.
I’m a crystallographer, which means I specialize in taking atomic resolution photographs of proteins. I became interested in solving the structure of KOR – when the protein is actually in its active state bound to a drug.
Structure is actually considered the gold standard for figuring out how a drug interacts which has a receptor along with produces a signal. To solve the KOR structure, I first manufactured the KOR protein to make KOR crystals, which consists of hundreds of millions of KOR molecules stacked from the same way, just like salt molecules in a salt crystal. Then I blasted the crystals with X-rays to generate an image of the receptor at atomic level. The key to these pictures was that will I “froze” the KOR proteins in their active state to understand how these receptors interact which has a drug.
With an action shot of KOR, we recognized what parts of the molecule are critical for blocking pain signals. We are currently using This kind of structural data to construct a “biased” molecule that will only activates the pain-blocking parts of the protein without triggering side effects.
Deciphering the structure of a protein is actually also valuable for creating a drug that will interacts only with only one receptor. All the members of the opioid receptor family – MOR, KOR along with DOR – look similar, like siblings. Therefore, these high-resolution photos are essential for designing drugs that will will only recognize along with target KOR.
Our structure is actually currently used for virtual drug screening where the computational program randomly inserts millions of compounds into the structure along with ranks each of them based on how well they fit. The better the score, the more likely that will compound will yield a drug.
The exciting news is actually that will researchers from the Roth lab have discovered several promising compounds based on the KOR structure that will selectively binds along with activates KOR, without cavorting with the more than 330 various other related protein receptors.
currently our challenge is actually to transform these molecules into safer drugs.