Structure-based design of multi-target drugs using the example of dual inhibitors of LTA4 hydrolase and soluble epoxide hydrolase

• Applicant: Professor Dr. Eugen Proschak
• Subject Area: Pharmacy
• Term: from 2012 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 225171069

Inflammation is a pathophysiological state controlled by multiple pathways. One of the central regulators of inflammatory processes is the arachidonic acid cascade, which controls the onset and the active resolution of inflammation. Dual or multi-target inhibitors of enzymes involved in the arachidonic acid cascade have several advantages compared with selective compounds, including improved efficacy and more simple pharmacokinetic and pharmacodynamic properties than a combination of several drugs. Unfortunately, the rational design of polypharmacological compounds is a rather hard task and not well established. In the first three years we developed a strategy for the identification of starting points for rational multi-target drug discovery discovering novel inhibitors of 5-lipoxygenase and soluble epoxide hydrolase. Based on these results, the aim of the proposed project is the rational optimization of multi-target leads, which will be applied to the design of dual inhibitors of soluble epoxide hydrolase and leukotriene A4 hydrolase. We assume that dual inhibition of both enzymes will lead to resolution of chronic inflammatory conditions by accumulation of anti-inflammatory lipid mediators.

• DFG Programme: Research Grants