| Literature DB >> 18052117 |
Rong-Jian Lu1, John A Tucker, Tatiana Zinevitch, Olga Kirichenko, Vitalii Konoplev, Svetlana Kuznetsova, Sergey Sviridov, Jason Pickens, Sagun Tandel, Enugurthi Brahmachary, Yang Yang, Jian Wang, Stephanie Freel, Shelly Fisher, Alana Sullivan, Jiying Zhou, Sherry Stanfield-Oakley, Michael Greenberg, Dani Bolognesi, Brian Bray, Barney Koszalka, Peter Jeffs, Alisher Khasanov, You-An Ma, Cynthia Jeffries, Changhui Liu, Tatiana Proskurina, Tong Zhu, Alexander Chucholowski, Rongshi Li, Connie Sexton.
Abstract
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.Entities:
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Year: 2007 PMID： 18052117 DOI： 10.1021/jm070650e
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446