title: Interfacial inhibitors.
abstract: Targeting macromolecular interface is a general mechanism by which natural products inactivate macromolecular complexes by stabilizing normally transient intermediates. Demonstrating interfacial inhibition mechanism ultimately relies on the resolution of drug-macromolecule structures. This review focuses on medicinal drugs that trap protein-DNA complexes by binding at protein-DNA interfaces. It provides proof-of-concept and detailed structural and mechanistic examples for topoisomerase inhibitors and HIV integrase inhibitors. Additional examples of recent interfacial inhibitors for protein-DNA interfaces are provided, as well as prospects for targeting previously 'undruggable' targets including transcription, replication and chromatin remodeling complexes. References and discussion are included for interfacial inhibitors of protein-protein interfaces.
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kiselev
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
mesh_terms: D001665:Binding Sites / Q000187:drug effects*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D026942:DNA Topoisomerases / Q000737:chemistry / Q000378:metabolism; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D046911:Macromolecular Substances; D059003:Topoisomerase Inhibitors; D004247:DNA; D019427:HIV Integrase; D026942:DNA Topoisomerases
keywords: Chemotherapy; Integrase; Natural products; Pharmacology; Topoisomerase