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RATIONAL DRUG DESIGN
In contrast to traditional methods of drug discovery which rely on trial-and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to treatments, rational drug design begins with a hypothesis that modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be selected as a drug target, two essential pieces of information are required.
- The first is evidence that modulation of the target will have therapeutic value. This knowledge may come from Xtal’s asay development services or prior knowledge.
- The second is that the target is "drugable". This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule. (Xtal’s biophysical services can be utilized to get to an answer.)
Once a suitable target has been identified by XTALor the client using pre-published or proprietary information, the target is normally cloned and expressed. The expressed target is then used to establish a screening assay. In addition, the three-dimensional structure of the target will be determined using X-ray Crystallography.
Drug design, also sometimes referred to as rational drug design, is the inventive process of finding new medications based on the knowledge of the biological target.The drug being developed is most commonly an organic small molecule which activates or inhibits the function of a biomolecule such as a protein target identified in the screening assay, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves design of small molecules that are complementary in shape and charge to the biomolecular target to which they interact and therefore will bind to it.
Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography . Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist. As experimental methods such as X-ray crystallography and NMR develop, the amount of information concerning 3D structures of biomolecular targets has increased dramatically.
The elucidation of the chemical structure is critical to avoid the re-discovery of a chemical agent that is already known for its structure and chemical activity. The end product is a new chemical entity (NCE) that can be used as the API for future pre-clinical activities. This generates valuable IP for the client.
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