title: Contributions of charge-density research to medicinal chemistry.
abstract: This article reviews efforts in accurate experimental charge-density studies with relevance to medicinal chemistry. Initially, classical charge-density studies that measure electron density distribution via least-squares refinement of aspherical-atom population parameters are summarized. Next, interaction density is discussed as an idealized situation resembling drug-receptor interactions. Scattering-factor databases play an increasing role in charge-density research, and they can be applied both to small-molecule and macromolecular structures in refinement and analysis; software development facilitates their use. Therefore combining both of these complementary branches of X-ray crystallography is recommended, and examples are given where such a combination already proved useful. On the side of the experiment, new pixel detectors are allowing rapid measurements, thereby enabling both high-throughput small-molecule studies and macromolecular structure determination to higher resolutions. Currently, the most ambitious studies compute intermolecular interaction energies of drug-receptor complexes, and it is recommended that future studies benefit from recent method developments. Selected new developments in theoretical charge-density studies are discussed with emphasis on its symbiotic relation to crystallography.
authors.affiliation: Institut für Anorganische und Angewandte Chemie, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
authors.forename: Birger
authors.initials: B
authors.lastname: Dittrich
authors.affiliation: Department of Chemistry and Physics, Mount Saint Vincent University, Halifax, Nova Scotia B3M 2J6, Canada ; Department of Chemistry, Dalhousie University, Halifax, Nova Scotia B3H 4J3M, Canada ; Department of Chemistry, Saint Mary's University, Halifax, Nova Scotia B3H 3C3, Canada.
authors.forename: Chérif F
authors.initials: CF
authors.lastname: Matta
keywords: Hansen–Coppens multipole model; charge-density research; drug design; invariom; medicinal chemistry; quantum theory of atoms in molecules