title: Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.
abstract: The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier.
authors.affiliation: 10 Connshire Drive, Waterford, CT 06385-4122, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lipinski
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry; D016572:Cyclosporine / Q000737:chemistry; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D000814:Aniline Compounds; D001688:Biological Products; D008024:Ligands; D004364:Pharmaceutical Preparations; D013449:Sulfonamides; D016572:Cyclosporine; C528561:navitoclax
keywords: Binding pockets in folded proteins; Biologically active chemistry space; Characteristics of protein ligands; H-bonding in natural products; Natural product chemistry synthons; Navitoclax a rule of 5 outlier; Protein binding pocket evolution; Shape change in natural products