Structure-guided selection of Specificity Determining Positions in the human kinome

It is well-known that inhibitors of protein kinases bind with very different selectivity profiles. This is also the case for inhibitors of many other protein families. A better understanding of binding selectivity would enhance the design of drugs that target only a subfamily, thereby minimizing possible side-effects. The increased availability of protein 3D structures has made it possible to study the structural variation within a given protein family. However, not every structural variation is related to binding specificity. We propose a greedy algorithm that computes a subset of residue positions in a multiple sequence alignment such that structural and chemical variation in those positions helps explain known binding affinities. By providing this information, the main purpose of the algorithm is to provide experimentalists with possible insights into how the selectivity profile of certain inhibitors is achieved, which is useful for lead optimization. In addition, the algorithm can also be used to predict binding affinities for structures whose affinity for a given inhibitor is unknown. The algorithm´s performance is demonstrated using an extensive dataset for the human kinome, which includes a large and important set of drug targets. We show that the binding affinity of 38 different kinase inhibitors can be explained with consistently high precision and accuracy using the variation of at most six residue positions in the kinome binding site.