title: A rapid alternative to X-ray crystallography for chiral determination: case studies of vibrational circular dichroism (VCD) to advance drug discovery projects.
abstract: The absolute stereochemistry of chiral drugs is usually established via X-ray crystallography. However, vibrational circular dichroism (VCD) spectroscopy coupled with quantum mechanics simulations offers a rapid alternative to crystallography and is readily applied to both crystalline and non-crystalline samples. VCD is an effective complement to X-ray analysis of drug candidates, and it can be used as a high-throughput means of assessing absolute stereochemistry at all phases of the discovery process (hundreds of assignments per year). The practical implementation (or fee-for-service outsourcing) of VCD and selected case studies are illustrated with an emphasis on providing utility and impact to pharmaceutical discovery programs.
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA. steven.wesolowski@azneuro.com
authors.forename: Steven S
authors.initials: SS
authors.lastname: Wesolowski
authors.forename: Don E
authors.initials: DE
authors.lastname: Pivonka
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry; D002942:Circular Dichroism / Q000295:instrumentation; D018360:Crystallography, X-Ray; D016202:N-Methylaspartate / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: C555357:3-((methylsulfonyl)amino)-2-phenyl-N-(1-phenylpropyl)quinolin-4-carboxamide; D000634:Aminoquinolines; D004364:Pharmaceutical Preparations; D018100:Receptors, Histamine H3; D013449:Sulfonamides; D016202:N-Methylaspartate