Kinases are an extensive class of enzymes affecting the substrates’ reactivity and binding properties and regulating the energy balance by catalyzing phosphorylation. Therefore, kinases are crucial to many phases of cell life. Modulators of protein kinase activity are firmly established as a significant class of drug targets for the pharmaceutical industry. Consistently high interest in this class of targets reflects both advances in identifying selective protein kinase inhibitors and a growing perception of the fact that these drugs offer a novel, well-tolerated oral therapy for some of the most untreatable cancers and immune disorders.
Life Chemicals has designed a proprietary Kinase Targeted Docking Library of over 13,000 drug-like screening compounds, using a receptor-based approach (docking-based virtual screening). This screening set is aimed at facilitating the efficiency of high-throughput screening projects in anticancer drug discovery. Our cheminformatics team has developed an original docking and scoring strategy to identify potentially active and selective kinase modulators on the base of crystal 3D structures of protein-ligand complexes of five molecular targets from different kinase families:
- CDK2 (cyclin-dependent kinase 2)
- GSK3 (glycogen synthase kinase 3)
- PKB (protein kinase B)
- SRC kinases (2 protein structures)
- EGFR (epidermal growth factor receptor)
Initially, the Life Chemicals HTS Compound Collection was filtered using the Lipinski Rule of Five and in-house MedChem filters, with toxicophore and undesired functionalities removed. 3D structures were generated in the SYBYL-X. The ligand dataset was prepared within the LigPrep program (Schrödinger software package). The protein-ligand structures recorded in the corresponding PDB entries [1-6] were analyzed and optimized in the SYBYL-X. Then the identification of the key residues and features of the ligands responsible for the binding was performed with the following grid maps generation of the binding sites. The docking process was carried out with the Glide docking tool, which provides exhaustive and tunable search based on constraints in electrostatic grid maps and hydrophobic regions. Validation of the protein binding site models and docking procedure was performed using a reference set of kinase inhibitors with known bioactivity data. Finally, the molecules for this Screening Library were selected according to score values related to the docking validation experiment results.
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