High throughput molecular reverse docking profiles and their applications

Abstract

Current computational state-of-the-art technology in drug development reaches the limit, so that whole cost of developing a drug have been increased steadily, and we are still far from substantial improvement of success rate. In early stage in drug discovery, the most common computational approach, virtual screening, aims to detect a novel ligand or small molecule that is most likely to bind to the protein target, which is responsible for a disease of interest. Virtual screening involves docking of a number of ligands into a target so as to find the ligand which will bind to the protein with high affinity. However, this screening method cannot handle and predict unexpected binding affinities to off-targets. Reverse docking approaches have been attempted in previous studies on drug discovery to overcome such issues in traditional virtual screening. However, the scales of current reverse docking approaches are relatively limited in that the protein-target spaces of those studies were rather small. Their applications are not quite sufficient for identifying new drug targets. In this thesis, the scope of target space has been expanded to a set of all X-ray protein structures currently available in two distinct species. Additionally several new applications of reverse docking method were developed. First, two-dimensional profile matrices of docking scores among structures in yeast and human proteome and 35 ligands were generated. By clustering the docking profile data and then comparing them with structural fingerprint-based clustering of drugs, it has been shown that the data contained accurate information on their chemical properties. Next, the docking profiles were used for further applications. The method could be utilized to predict the druggability of target proteins. Also, a simple combination of sequence similarity and docking profile similarity could improve the accuracy of prediction of the enzyme EC numbers, indicating the function of enzymes, more than ...