De novo design of multitarget ligands with an iterative fragment-growing strategy.

The discovery of multitarget drugs has recently attracted much attention. Most of the reported multitarget ligands have been serendipitous discoveries. Although a few methods have been developed for rational multitarget drug discovery, there is a lack of elegant methods for de novo multitarget drug design and optimization, especially for multiple targets with large differences in their binding sites. In this paper, we report the first de novo multitarget ligand design method, with an iterative fragment-growing strategy. Using this method, dual-target inhibitors for COX-2 and LTA₄H were designed, with the most potent one inhibiting PGE₂ and LTB₄ production in the human whole blood assay with IC₅₀ values of 7.0 and 7.1 μM, respectively. Our strategy is generally applicable in rational and efficient multitarget drug design, especially for the design of highly integrated inhibitors for proteins with dissimilar binding pockets.