Specificity rendering ‘hot-spots’ for aurora kinase inhibitor design: the role of non-covalent interactions and conformational transitions

Abstract

The present study examines the conformational transitions occurring among the major structural motifs of Aurora kinase (AK) concomitant with the DFG-flip and deciphers the role of non-covalent interactions in rendering specificity. Multiple sequence alignment, docking and structural analysis of a repertoire of 56 crystal structures of AK from Protein Data Bank (PDB) has been carried out. The crystal structures were systematically categorized based on the conformational disposition of the DFG-loop [in (D_I) 42, out (D_O) 5 and out-up (D_OU) 9], G-loop [extended (G_E) 53 and folded (G_F) 3] and αC-helix [in (C_I) 42 and out (C_O) 14]. The overlapping subsets on categorization show the inter-dependency among structural motifs. Therefore, the four distinct possibilities a) 2W1C (D_I, C_I, G_E) b) 3E5A (D_I, C_I, G_F) c) 3DJ6 (D_I, C_O, G_F) d) 3UNZ (D_OU, C_O, G_F) along with their co-crystals and apo-forms were subjected to molecular dynamics simulations of 40 ns each to evaluate the variations of individual residues and their impact on forming interactions. The non-covalent interactions formed by the 157 AK co-crystals with different regions of the binding site were initially studied with the docked complexes and structure interaction fingerprints. The frequency of the most prominent interactions was gauged in the AK inhibitors from PDB and the four representative conformations during 40 ns. Based on this study, seven major non-covalent interactions and their complementary sites in AK capable of rendering specificity have been prioritized for the design of different classes of inhibitors.