Assessing the structural conservation of protein pockets to study functional and allosteric sites: implications for drug discovery

We performed a large-scale study of protein cavities as potential allosteric and functional sites, by integrating publicly available information on protein sequences, structures and active sites for more than a thousand protein families. By identifying common pockets across different structures of the same protein family we developed a method to measure the pocket's structural conservation. The method was first parameterized using known active sites. We characterized the predicted pockets in terms of sequence and structural conservation, backbone flexibility and electrostatic potential. Although these different measures do not tend to correlate, their combination is useful in selecting functional and regulatory sites, as a detailed analysis of a handful of protein families shows. We finally estimated the numbers of potential allosteric or regulatory pockets that may be present in the data set, finding that pockets with putative functional and effector characteristics are widespread across protein families.Our results show that structurally conserved pockets are a common feature of protein families. The structural conservation of protein pockets, combined with other characteristics, can be exploited in drug discovery procedures, in particular for the selection of the most appropriate target protein and pocket for the design of drugs against entire protein families or subfamilies (e.g. for the development of broad-spectrum antimicrobials) or against a specific protein (e.g. in attempting to reduce side effects).Molecular processes in the living cell are coordinated and executed under tight regulation. Proteins play a fundamental role in almost all biological processes, and their overall activity is regulated at different levels [1]. At a first level, the concentration of a particular protein in the cell is regulated through its synthesis rate (gene expression) and its degradation rate. At another level, mechanisms act on the protein molecule itself through covalent mo