Leukotriene A4 (LTA4) Inhibitors Library

Leukotriene A4 hydrolase is a zinc-containing enzyme which can stereospecifically catalyze the hydrolysis of epoxide LTA4 to the diol leukotriene B4 (LTB4). There is substantial evidence that LTB4 plays an important role in the amplification of many inflammatory disease states. Therapeutic agents that selectively inhibit LTA4 hydrolase will block the formation of LTB4, and therefore be potentially useful for the treatment of inflammation. LTA4 has been applied as an important anti-inflammatory target. In general, the design of LTA4 hydrolase inhibitors is developed based on the structure of the natural substrate, LTA4.

BOC Sciences is committed to designing a library of LTA4 inhibitors that will provide the next generation of peptide and non-peptide analogs that contain potential zinc-chelating moieties, including thiols, hydroxamates, and norstatines.

Figure 1. Structure of the captopril-LTA4H complex. (Thunnissen, M.; et al. 2002)

Library Design

BOC Sciences has applied both structure-based and ligand-based approaches to generate docking models

1. We screen the commercial databases against LTA4H by X-ray crystallography comprehensively
• Literature data and activity of the drug are fully considered
2. Metal binding sites of the ligands, hydrophobic regions and H-bonds that form with protein molecules are employed to generate accurate and detailed docking
• A diverse set of fragments including derivatives of resveratrol, nicotinamide and indole are identified as active ligands for LTA4H

BOC Sciences also supports vector machines (SVM), random forests (RF) and K-nearest neighbors (KNN) methods to construct 18 classification models for over 460 LTA4H inhibitors

• The best classification models are constructed based on RF and MACCS fingerprints
• K-Means are utilized to divide these LTA4H inhibitors into six subsets
• The highly active LTA4H inhibitors mostly contain diphenylmethane or diphenyl ether as the scaffold and pyridine or piperidine as the side chain
3. In addition, six quantitative structure-activity relationship (QSAR) models for the LTA4H inhibitors are built using multiple linear regression (MLR) and SVM
4. The coefficients of determination of the training test and the test sets are equal to 0.81 and 0.79, respectively

Figure 2. Comparison of inhibitor binding at the active site of thermolysin (blue) and LTA4H (red). (Thunnissen, M.; et al. 2002)

LTA4 Inhibitors Library Characteristics

• 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 Leukotriene A4 (LTA4) Inhibitors Library design at competitive prices for global customers. Personalized and customized services of Leukotriene A4 (LTA4) Inhibitors 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!