The virtual dynamic docking, carried out in the MOLBD3 lab of the Institute of Biophysics, allows the identification of new drugs through the structural information deriving from the study of target proteins, responsible for some human pathologies. In particular, we screen drugs or small molecules (commercial/own libraries) against known protein sites, surface cavities, surfaces of protein-protein interactions (fixed/rigid hotspots) or structural transition states (dynamic hotspots). The identification of hotspots takes place through structural analysis and molecular dynamics simulations. High throughput (HT) approaches have great potential as they are based on high computational capacity. In this context, our skills supervise the calculation methods and support the interpretation of the large amount of HT data, directing the research in a more focused way. This approach allows to map in detail the configurations of the target protein regions, significantly expanding the possibilities of identifying effective drugs.
The innovative aspect lies in the study of the dynamics of proteins related to their functions. Not only the average structure of a protein (obtained through different experimental methods) but also transient sites and cavities, such as those involving intermediate folding states or conformational transitions identifiable by molecular dynamics, are considered as target surfaces. Since intermediate folds only exist for a short time, they can be difficult to study experimentally. Through advanced algorithms and computational simulations it is possible to model the folding trajectory of a protein, thus identifying transient forms that could bind to new drugs with high affinity and specificity. In a biological context with single molecule resolution, copies of the same protein are fewer and immersed in a complex context of different macromolecules. In this condition, transient states could play a much more important role than hypothesized. This approach provides the ability to transform proteins that may be difficult to pharmacologically target with ordinary methods, into drug targets.