Protein kinase ERK5, also known as mitogen-activated protein kinase 7 (MAPK7), is an emerging drug target for a variety of indications, in particular, for cancer where it plays a key role in mediating cell proliferation, survival, epithelial-mesenchymal transition and angiogenesis.
To design a ERK5 (MAPK7) Kinase Targeted Library, reported 4IC7  and 4B99  PDB entries were used as spatial structures for docking. Glide docking program (Schrödinger software) was used for screening procedure. Validation of two docking models (prepared on the basis of 4IC7 and 4B99) was conducted. The 4IC7 structure showed a better reproducibility for co-crystallized ligand conformation - RMSD value between crystallographic conformation of the ligand (ANP) and the best docked pose is 0.6Å. Thereafter, 36 known inhibitors of ERK5 reported in ChEMBL (with IC50<1µM) were taken as reference molecules for optimization and validation of the docking procedure. The Life Chemicals Stock Collection was filtered using toxicity and undesired groups filtering parameters, PAINS filters were also applied. A diversity set of 50,000 structures based on compounds that passed the filtering was created.
Description of the docking procedure:
The following features and constraints were defined from the ligand and binding site as important for ligand bindings: purine moiety from the ligand was identified as hydrophobic (aromatic) feature; a set of residues was indicated as responsible for hydrogen bonding: Met140, Asp200, Glu102, Gln146, Asp143, Arg98, Ala65, Lys84, Arg125, Asp138, Ser71; electrostatic map of the binding pocket was generated within default parameters, including hydrophobicity and active residues. Thereafter, the docking was launched with a sequential screening transition from a high throughput (HTS) to standard docking procedure (SP) (Fig.1).
Results of the docking were evaluated by Gscore and Emodel scoring functions. Results of the screening correlated well with the biological data of the reference set of compounds with known ERK5 inhibitory activity.
About 900 compounds were predicted as possessing high binding affinity towards the active site of ERK5 (Fig.2, 3).
|Fig.1. Example of binding conformation of a ligand from the set of screened molecules. The ligand forms hydrogen bonds with Asp143, Lys84 and Arg125. Strong hydrophobic interaction observed between linked phenyl ring of the ligand and hydrophobic region of ERK5.|
|Fig.2. Binding conformation of compound F6200-2411 in ERK5 active site. Gscore = -8.33; Emodel = -79.49. Mole-cule forms two hydrogen bonds with Lys84 and one water-mediated hydrogen bond with Glu102; it also has good shape complementarity to the binding site.||Fig.3. Binding conformation of compound F6230-0364 in ERK5 active site obtained with docking. Gscore = -8.22; Emodel = -62.56. Ligand forms strong hydrogen bond with Met140 (d =1.9 Å) and water-mediated hydrogen bond with Glu102.|