Docking-based Kinase Targeted Library

Kinases are a class of enzymes that are capable of affecting the substrates’ reactive and binding properties and regulating the energy balance by catalyzing phosphorylation. Thus, kinases are essential for many stages of cellular life. Modulators of protein kinase activity have been considered as an important class of drug targets, and the identification of selective protein kinase inhibitors is therefore a challenging task for academia. In addition, it is increasingly recognized that these drugs offer a new, well-tolerated oral therapy for some of the most incurable cancers and immune diseases. Small molecule kinase inhibitors are convenient to administer orally and have better tissue penetration, thus offering advantages over large molecule biologics. However, designing kinase inhibitors with target selectivity and minimal off-target effects is a very challenging task. Great progress has been made in the development of some kinase inhibitors such as JAKs, IRAK4, RIPKs, BTK, SYK and TPL2.

BOC Sciences can apply a receptor-based approach (docking-based virtual screening) to design a proprietary kinase-targeted docking library containing over 13,000 drug-like screening compounds.

Figure 1. Docked poses of tyrosine kinase domain from epidermal growth factor receptor with the co-crystallized aminopterin derivative 3 ligand. (Ebuka, A. D.; et al. 2018)

Docking-based Kinase Targeted Library Design

BOC Sciences has designed and employed a high-throughput docking strategy to filter in silico compounds and generate kinase targeted libraries. Our cheminformatics teams have developed a novel docking and scoring strategy to identify potentially active and selective kinase modulators on the crystal 3D structural motifs 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)

Design Workflow

1. Firstly, the BOC Sciences HTS compound collection is filtered using Lipinski's Rule of Five and internal filters to remove toxic substances with unwanted functions
2. Then, 3D structures of kinase ligands with different structures and other data sets are prepared, and the corresponding protein-ligand structures are analyzed and optimized
3. Next, we perform a systematic docking and scoring in these 3D structures to generate correct binding sites to identify key residues and features of the ligands responsible for binding. The docking process is completed using the Glide docking tool, which provides an exhaustive and tunable search based on constraints in electrostatic lattice maps and hydrophobic regions. The determination of six thresholds for each kinase is also generated
4. These thresholds are then used as filters for the virtual screening of the compound collection, resulting in a collection of over 2500 drug and drug-like compounds and a kinase targeted library of 1440 compounds
5. The protein binding site models and docking procedures will be further validated using a data set of reference kinase inhibitors with known bioactivity information
6. Finally, molecules for this screening library are successfully selected based on scoring values associated with the results of docking validation experiments

Figure 1. Docked poses of tyrosine kinase domain. (Ebuka, A. D.; et al. 2018)

Docking-based Kinase Targeted Library Characteristics

• Our docking-based kinase-targeted libraries can be used for the identification of scaffolds with high kinase inhibitory potential
• Favorable physicochemical parameters and solubility requirements
• No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
• Bioactivity and safety confirmed by preclinical studies and clinical trials
• Structural diversity, medicinal activity, and cellular penetration
• Structural document, IC₅₀, and other chemical and biological data are provided
• All compounds are continually updated
• Compound cherry-picking service is provided

What We Deliver

• Delivered within 2 weeks in any customer-preferred format
• Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
• All compounds have a minimum purity of 90% assessed by ¹H NMR and HPLC
• Analytical data is provided

BOC Sciences provides professional, rapid and high-quality services of Docking-based Kinase Targeted Library design at competitive prices for global customers. Personalized and customized services of Docking-based Kinase Targeted Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!