Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

The development of multitarget-directed ligands (MTDLs) has become a widely focused research topic, but rational design remains as an enormous challenge. This paper reviews and discusses the design strategy of incorporating the second activity into an existing single-active ligand. If the binding sites of both targets share similar endogenous substrates, MTDLs can be designed by merging two lead compounds with similar functional groups. If the binding sites are large or adjacent to the solution, two key pharmacophores can be fused directly. If the binding regions are small and deep inside the proteins, the linked-pharmacophore strategy might be the only way. The added pharmacophores of second targets should not affect the binding mode of the original ones. Moreover, the inhibitory activities of the two targets need to be adjusted to achieve an optimal ratio.

Automated summary

The development of multitarget-directed ligands (MTDLs) is a widely focused research topic, but rational design remains a challenge. Strategies for designing MTDLs include merging lead compounds with similar functional groups, fusing key pharmacophores directly, and using the linked-pharmacophore strategy. The pharmacophores of second targets should not affect the binding mode of the original ones, and the inhibitory activities of the two targets need to be adjusted.