3.5. Docking Study

The computational study i.e., molecular docking study, was started by sketching the2D form of the structures of all synthesized compounds using the sketch modules of SYBYL-X 2.1.1. 2D [58] formss of the compounds then subjected to the ligand library preparation module by keeping the preparation protocol as surface for searching where it generates a single lowest strain energy tautomer/stereoisomer and all necessary structural properties were added and finally a 3D prepared conformation of each compounds was stored in SYBYL-Mol2 file format. To perform molecular docking a three dimensional X-ray crystal structure of tubulin (PDB ID: 1SA0 Resolution 3.58 Å) [59] complex with colchicine was used. Many TRK inhibitors (TRKs) have been produced and tested in the clinic by now. The crystal structures of c-kit receptor protein-tyrosine kinase in complex with STI-571 (imatinib or Gleevec) were picked from the Protein Data Bank (PDB) (http://www.rcsb.org/pdb/explore/explore.dostructureId=1T46) (PDB code: 1t46). The synthesized compounds 4(a–n) were subjected to a molecular docking study performed with the Surflex-Dock module of the Sybyl2.1.1 package following standard procedures for understanding the binding interactions with human TRKs1 enzyme (PDB ID: 1t46). All the synthesized compounds showed very good binding interactions in the active site of the selected receptors. The most active compounds from the synthesized series which have exhibited very high docking scores value against selected receptors and had a good binding affinity predicated by non-covalent interactions such as hydrogen bond interaction, VDW interaction, carbon, hydrogen bond interaction, π-Anion interaction, π-π shaped interaction, alkyl interaction, π-σ and π-alkyl interactions. To represent the details of docking score the following terms is used as total score: crash score: as the degree of inappropriate penetration by the ligand into the protein and of interpenetration between ligand atoms that are separated by rotatable bonds of compounds and polar-score which gives an idea about the contribution of the polar non-hydrogen bonding interactions to the total score, as shown in Table 3 and Table 4.