The importance of QSAR studies in pre-clinical phase of drug discovery

QSAR is the acronym of quantitative structure activity relationship, is a modern tool to discover new molecules that could become drug. Indeed, a crucial step in the drug discovery process is the identification of lead compound, the first molecule that has an activity on the target and could be modified to improve its pharmaceutical features. Molecular modeling allows to show how this lead fits into the target, for instance a protein, and defines what are the important bonds that guarantee the interaction. The three-dimensional structure of the target is essential to perform this kind of studies and obtain results pretty sure.

It’s not a case that the major pharmaceutical companies have large structural and biochemical group in their Research & Development department. Anyway, an hypothetical model, based on structures of other protein similar to those of interest, can be build and tested: is the robustness of the model that determine the quality of the prediction. Indeed, in both cases virtual model can be used to screen libraries and identify the most promising compounds, named lead. Then, these molecules are tested in biochemical or biological assays to validate the activity. In this way, only few molecules of thousands that compose a library, can reach the bench and can be screened, by effectively reducing costs. Modifications of an active lead compound are crucial to improve its pharmaceutical properties and increase the likelihood to successfully enter in clinical phases. QSAR identifies all the positions that are important for the interaction between compound and target and suggests some chemical groups that could be inserted to further stabilize this binding. Thus, other compounds derive from this virtual study that have to be validated in experimental conditions. By analyzing the changes in the activities, it’s possible to define a quantitative relationship between structure modifications and activity itself.

Modifications that show an improvement in the activity are selected and further compounds are synthesized, by combining these changes. Again, a virtual screening is firstly run to check the new binding modalities and, then, experiments determine the activity. By repeating this process two or three times it’s possible to dispose on leads of second and third generation that have more chances to become drug. This pre-clinical phase could take some years, but efficiently reduces the cost of drug discovery. Indeed, the high rate of failure in the clinical phases, the most expensive part of the process, in part depends on the lack of accurate pre-clinical studies. QSAR is one of the tool now available to reduce the failure rate and identify only the compounds that could potentially have success. However, the results from clinical studies are always the limiting step to the entrance on the market of novel drugs.