Structure-Activity Relationships and Molecular Docking of Novel Dihydropyrimidine-Based Mitotic Eg5 Inhibitors

• Published in: ChemMedChem Vol. 5; no. 10; pp. 1760 - 1769
• Main Authors: Prokopcová, Hana, Dallinger, Doris, Uray, Georg, Kaan, Hung Yi Kristal, Ulaganathan, Venkatasubramanian, Kozielski, Frank, Laggner, Christian, Kappe, C. Oliver
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 04.10.2010; WILEY‐VCH Verlag
• Subjects: Binding Sites; cancer; Computer Simulation; Crystallography, X-Ray; dihydropyrimidines; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Kinesin - antagonists & inhibitors; Kinesin - metabolism; kinesin inhibitors; Mitosis; molecular docking; multicomponent reactions; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000252

Dihydropyrimidine‐based compounds belong to the first discovered inhibitors of the human mitotic kinesin Eg5. Although they are used by many research groups as model compounds for chemical genetics, considerably less emphasis has been placed on the improvement of this type of inhibitor, with the exception of two recent studies. Dihydropyrimidines can be divided into class I (analogues that bind in the S configuration) and class II type inhibitors, which bind in the R configuration. Herein we report the synthesis and optimization of novel class II type dihydropyrimidines using a combination of in vitro and docking techniques. A welcome improvement: Fluorastrol is a novel Eg5‐specific inhibitor that was identified by a combination of in vitro screening and docking techniques. The compound belongs to the so‐called class II type dihydropyrimidines and binds preferentially in the R configuration to the Eg5 protein. The presence of fluorine atoms is believed to enforce multipolar interactions with the surrounding protein, making fluorastrol a better inhibitor than its parent compound.