Lu Rong-Jian, Tucker John A, Zinevitch Tatiana, Kirichenko Olga, Konoplev Vitalii, Kuznetsova Svetlana, Sviridov Sergey, Pickens Jason, Tandel Sagun, Brahmachary Enugurthi, Yang Yang, Wang Jian, Freel Stephanie, Fisher Shelly, Sullivan Alana, Zhou Jiying, Stanfield-Oakley Sherry, Greenberg Michael, Bolognesi Dani, Bray Brian, Koszalka Barney, Jeffs Peter, Khasanov Alisher, Ma You-An, Jeffries Cynthia, Liu Changhui, Proskurina Tatiana, Zhu Tong, Chucholowski Alexander, Li Rongshi, Sexton Connie
Trimeris, Inc., 3500 Paramount Parkway, Morrisville, North Carolina 27560, USA.
J Med Chem. 2007 Dec 27;50(26):6535-44. doi: 10.1021/jm070650e. Epub 2007 Dec 4.
The crystal structures of many tertiary alpha-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the alpha-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed a single conformation of each that gave significantly better overlap of key pharmacophore features than other conformations and thus suggest a possible binding conformation for each class.
许多叔α-酮酰胺的晶体结构显示出两个羰基呈正交排列。基于α-酮酰胺HIV附着抑制剂BMS 806（原BMS378806，26）可能通过类似构象与其gp120靶点结合的假设，我们设计并合成了一系列类似物，其中酮酰胺基团被等排磺酰胺基团取代。这些类似物中最有效的14i在M33假型抗病毒试验中显示出与26相当的抗病毒效力。酮酰胺抑制剂与磺酰胺抑制剂的柔性重叠计算显示，每种抑制剂的单一构象能使关键药效团特征的重叠比其他构象显著更好，因此表明了每一类抑制剂可能的结合构象。
