UC San Diego

Death associated protein kinase 2 (DAPK2) is a serine threonine kinase with 370 amino acid residues, whose structure is highly conserved with the other members in the death associated protein kinase (DAPK) family. To find out the inhibitors with high specificity to DAPK2, structural based virtual screening was carried out. According to the results of docking, ligand clustering, MM/GBSA analysis and position of ligands in the DAPK2 binding pocket, it can be concluded that DA7, whose binding affinity and MM/GBSA score are -11.7 Kcal/mol and -47.5 Kcal/mol respectively, is the most ideal candidate so far for DAPK2.

Engulfment and cell motility 1 protein (ELMO1) is a human protein regulated by ELMO1 gene, with 720 residues in total, which is critical in clearing the apoptotic germ cells in vivo.  Dedicator of cytokinesis 2 (DOCK2) is a guanine nucleotide exchange factor with a mass of 213 kDa, which is responsible for the activation of the chemotaxis process. DOCK2 and ELMO1 form a large, rigid complex via the SH3 domain at DOCK2 or the formation of the five-bundle helices by ELMO1 and DOCK2. To identify the potent inhibitors that interrupt the formation of the ELMO1-DOCK2 complex, both structural- and ligand- based virtual screening were carried out at the two potential pockets: one is located at the SH3 domain of DOCK2 and the other is located between the 5-helix bundles. From thedocking results, ZINC22013692 and ZINC48368120 were candidates with the highest binding affinity for the pocket at the SH3 domain and 5-helix bundles respectively