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Interfacial inhibitors

Yves Pommier¹, Evgeny Kiselev¹, Christophe Marchand¹

¹Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States.

Bioorganic & Medicinal Chemistry Letters

|August 4, 2015

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.

Keywords:

Chemotherapy Integrase Natural products Pharmacology Topoisomerase

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