title: How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets.
abstract: To improve discovery of drugs for difficult targets, the opportunities of chemical space beyond the rule of 5 (bRo5) were examined by retrospective analysis of a comprehensive set of structures for complexes between drugs and clinical candidates and their targets. The analysis illustrates the potential of compounds far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.
authors.affiliation: Department of Chemistry-BMC, Uppsala University , Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Doak
authors.affiliation: Department of Chemistry-BMC, Uppsala University , Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Chemistry-BMC, Uppsala University , Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Doreen
authors.initials: D
authors.lastname: Dobritzsch
authors.affiliation: Department of Chemistry-BMC, Uppsala University , Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
mesh_terms: D000818:Animals; D062126:Databases, Chemical; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D011485:Protein Binding; D011955:Receptors, Drug / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*
chemical_list: D008024:Ligands; D011955:Receptors, Drug