Computer-Aided Fragment Growing Strategies to Design Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase

Lena Hefke; Kerstin Hiesinger; W Felix Zhu; Jan S Kramer; Ewgenij Proschak

doi:10.1021/acsmedchemlett.0c00102

Computer-Aided Fragment Growing Strategies to Design Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase

ACS Med Chem Lett. 2020 Apr 8;11(6):1244-1249. doi: 10.1021/acsmedchemlett.0c00102. eCollection 2020 Jun 11.

Authors

Lena Hefke¹, Kerstin Hiesinger¹, W Felix Zhu¹, Jan S Kramer¹, Ewgenij Proschak¹

Affiliation

¹ Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Strasse 9, D-60438 Frankfurt, Germany.

Abstract

Multitarget ligands are interesting candidates for drug discovery and development due to improved safety and efficacy. However, rational design and optimization of multitarget ligands is tedious because affinity optimization for two or more targets has to be performed simultaneously. In this study, we demonstrate that, given a molecular fragment, which binds to two targets of interest, computer-aided fragment growing can be applied to optimize compound potency, relying on either ligand- or structure-derived information. This methodology is applied to the design of dual inhibitors of soluble epoxide hydrolase and leukotriene A4 hydrolase.