G protein-coupled receptors (GPCRs) characterize the largest class of cell surface receptors in humans. Due to their major role in the regulation of various physiological processes, they represent the largest class of targets for approved drugs. However, lack of selectivity of ligands due to the intertwining of homologous ligand binding sites across diverse subfamilies still remains a challenge.<br/><br/>The architectural organization of macrocycles allows them to compromise between structural pre-organization and sufficient adaptability to accommodate the facet of protein binding sites.Although not strictly following the "rule of five," macrocycles managed to obtain good cell permeability, enhanced metabolic steadiness, and address protein-protein interaction with low entropic cost.<br/><br/>To create and visualize the interaction landscape between macrocycles and GPCRs, we created a fully automatized KNIME workflow capable of retrieving, interpreting, and visualizing the interaction landscape between macrocycles and GPCRs using data from ChEMBL v28. Out of 793.749 compound-target interaction data pairs, 19.046 comprise at least one macrocycle with a ring size of 9 to 30. Duplicate removal revealed 3.348 unique compounds interacting with 96 GPCRs (out of 411 GPCRs). The most diverse targets are Somatostatin receptors 1, 4, and 3, covering 25, 23, and 21 distinctive scaffolds, respectively. Only 2% of one-ring macrocycles are cyclopeptides, while 80% of IC50 values for one-ring macrocycles are &lt; 1µM. Structural and physicochemical examination of the compounds demonstrated notable contrasts in their profiles.

Fully automatized KNIME workflows for analyzing macrocyclic ligands of GPCRs

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