期刊
ADVANCED DRUG DELIVERY REVIEWS
卷 101, 期 -, 页码 34-41出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.addr.2016.04.029
关键词
Biologically active chemistry space; Binding pockets in folded proteins; Protein binding pocket evolution; Characteristics of protein ligands; Natural product chemistry synthons; Shape change in natural products; H-bonding in natural products; Navitoclax a rule of 5 outlier
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 biosyhthesized 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. (C) 2016 Elsevier B.V. All rights reserved.
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