Biophysical Fragment Screening of the 尾1-Adrenergic Receptor: Identification of High Affinity Arylpiperazine Leads Using Structure-Based Drug Design

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• 作者：John A. Christopher ; Jason Brown ; Andrew S. Dor茅 ; James C. Errey ; Markus Koglin ; Fiona H. Marshall ; David G. Myszka ; Rebecca L. Rich ; Christopher G. Tate ; Benjamin Tehan ; Tony Warne ; Miles Congreve
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：56
• 期：9
• 页码：3446-3455
• 全文大小：490K
• 年卷期：v.56,no.9(May 9, 2013)
• ISSN：1520-4804

文摘

Biophysical fragment screening of a thermostabilized 尾₁-adrenergic receptor (尾₁AR) using surface plasmon resonance (SPR) enabled the identification of moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed the activity of the chemotype, and a structure-based design approach using protein鈥搇igand crystal structures of the 尾₁AR resulted in the identification of several fragments that bound with higher affinity, including indole 19 and quinoline 20. In the first example of GPCR crystallography with ligands derived from fragment screening, structures of the stabilized 尾₁AR complexed with 19 and 20 were determined at resolutions of 2.8 and 2.7 脜, respectively.