Edin Muratspahić, Kristine Deibler, Jianming Han, Nataša Tomašević, Kirtikumar B Jadhav, Aina-Leonor Olivé-Marti, Nadine Hochrainer, Roland Hellinger, Johannes Koehbach, Jonathan F Fay, Mohammad Homaidur Rahman, Lamees Hegazy, Timothy W Craven, Balazs R Varga, Gaurav Bhardwaj, Kevin Appourchaux, Susruta Majumdar, Markus Muttenthaler, Parisa Hosseinzadeh, David J Craik, Mariana Spetea, Tao Che, David Baker, Christian W Gruber
Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities...
December 6, 2023: Nature Communications