The development of selective modulators of channels and transport proteins that represent potential drug targets is of primary importance to the NCCR TransCure network.
The group of Reymond will apply ligand-based computer-aided drug design starting from known, generally non-selective channel/transporter modulators to screen compound databases in silico for related ligands with a similar or better activity than the initial compounds. An in-house developed and validated high-throughput virtual screening method will be used to select promising test compounds, which will be acquired and subjected to in vitro functional assays in collaboration with other groups in the network. The group will use this approach to a diverse array of channels and transporters currently being investigated within TransCure, including TRPV6, TRPC1, and TRPM4 of the TRP channel superfamily, amino acid transporters, DMT1, NCX, NHA2, GLUT9, the putative endocannabinoid transporter, and others.
Based on the results of the above described computer-aided screening campaigns in combination with in vitro functional testing of the compounds, synthetic hit-to-lead chemistry is initiated for promising hit structures. If hits can be successfully developed into leads, this will result in a lead optimization program to produce compounds with adequate PK profiles and in vivo activity.