Structure based drug discovery facilitated by crystallography
Drugs exert therapeutically meaningful effects if they bind with appropriate selectively and potency to their respective targets. Although many of the assay techniques employed in early-stage drug discovery provide evidence that a drug is acting upon the target under investigation, this is often indirect and the site of action and stoichiometry is unknown…
Even incisive techniques such as surface plasmon resonance (SPR) and isothermal titration calorimetry do not provide absolute evidence that the compound is interacting with the target in the desired manner. This article explains how the gap can be filled by crystallography.
Resolving the atomic structure of a protein with a compound not only confirms target binding but also provides structural information on the location of the binding site and the precise nature of the interactions between the drug’s functional groups and the amino acids in the protein which are important for binding. These results can be used to help explain the basis of effective inhibition and to improve the potency and specificity of compounds in the drug discovery workflow. Structure based drug discovery (SBDD) has become an important element of medicinal chemistry projects, but until recently has often been limited due to its low throughput and applicability for soluble targets only.