Electron Density Guided Fragment-Based Lead Discovery of Ketohexokinase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 53; no. 22; pp. 7979 - 7991
• Main Authors: Gibbs, Alan C, Abad, Marta C, Zhang, Xuqing, Tounge, Brett A, Lewandowski, Francis A, Struble, Geoffrey T, Sun, Weimei, Sui, Zhihua, Kuo, Lawrence C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.11.2010; Amer Chemical Soc
• Subjects: AFFINITY; Animals; BASIC BIOLOGICAL SCIENCES; Caco-2 Cells; Cell Membrane Permeability; Chemistry, Medicinal; CRYSTALLOGRAPHY; Crystallography, X-Ray; DESIGN; ELECTRON DENSITY; Electrons; Fructokinases - antagonists & inhibitors; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; Humans; In Vitro Techniques; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacokinetics; Life Sciences & Biomedicine; Male; Microsomes, Liver - metabolism; Models, Molecular; Molecular Structure; MOLECULAR WEIGHT; Pharmacology & Pharmacy; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacokinetics; PROTEINS; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; SYNTHESIS; TARGETS; COMPLEX; X-RAY CRYSTALLOGRAPHY; ACCURATE DOCKING; CRYSTAL-STRUCTURE; PURIFICATION; FORCE-FIELD; ASSAYS; GLIDE; HUMAN ADENOSINE KINASE; RIBOKINASE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100677s

A fragment-based drug design paradigm has been successfully applied in the discovery of lead series of ketohexokinase inhibitors. The paradigm consists of three iterations of design, synthesis, and X-ray crystallographic screening to progress low molecular weight fragments to leadlike compounds. Applying electron density of fragments within the protein binding site as defined by X-ray crystallography, one can generate target specific leads without the use of affinity data. Our approach contrasts with most fragment-based drug design methodology where solution activity is a main design guide. Herein we describe the discovery of submicromolar ketohexokinase inhibitors with promising druglike properties.