Abstract
The (thio)carboxanilide derivatives are potent and selective inhibitors of HIV-1 reverse transcriptase (RT) and have a favourable antiviral activity spectrum. To understand better their mode of action, and to provide a structural basis for further improvement, models of RT complexed with four (thio)carboxanilide inhibitors (UC781, UC10, UC38 and UC84) have been constructed based on the X-ray structure of RT complexed with 9-chloro-TIBO. In the models, the protein conformation is similar to that of the RT-TIBO complex and the complexes are stabilised by hydrogen bonding between the inhibitors and the main chain oxygen of Lys101. Significant hydrophobic interactions include those with Leu100, Val106, Val179, Tyr188, Phe227, Leu234, and His235. The thiocarboxanilides UC781 and UC10 also make important hydrophobic interactions with Trp229. The models are consistent with the inhibitors' relative antiviral potencies and the observed resistance data. They further predict that mutations to Phe227, Trp229, or Leu234 might confer resistance. Since these are not observed, some constraining structural or functional role for these residues in the active enzyme is suggested.
Citations
Oct 24, 2007·Journal of Chemical Information and Modeling·Gabriela BarreiroWilliam L Jorgensen
Jan 31, 2012·Journal of Medicinal Chemistry·Xiaowei WangJunyi Liu
Sep 18, 2001·AIDS Research and Human Retroviruses·K SuzukiD A Cooper
Mar 10, 1998·AIDS Research and Human Retroviruses·J BalzariniE De Clercq
Jun 21, 2001·Proceedings of the National Academy of Sciences of the United States of America·G TachedjianS P Goff
May 13, 1999·Il Farmaco·E De Clercq
Jun 3, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Liang ZhangXiaowei Wang
Oct 13, 2006·Organic & Biomolecular Chemistry·Xiaowei WangJunyi Liu
Sep 8, 2000·Archives of Pharmacal Research·H G HahnK J Whang
Jul 18, 2002·Nature Reviews. Drug Discovery·Erik De Clercq
Jul 24, 1998·AIDS·J BalzariniE De Clercq
Nov 28, 2000·Molecular Pharmacology·B DegrèveJ Balzarini
Mar 28, 1998·Antimicrobial Agents and Chemotherapy·M WitvrouwE De Clercq
Mar 21, 2008·Journal of Chemical Information and Modeling·Kirstin MoffatAndrew R Leach
Jul 31, 2008·Journal of Medicinal Chemistry·Jingshan RenDavid K Stammers
Feb 7, 1998·Journal of Molecular Biology·G MagaS Spadari
Oct 1, 1998·Antiviral Research·E De Clercq
Oct 3, 1999·Journal of Medicinal Chemistry·J RenD K Stammers
Feb 6, 2004·Journal of Medicinal Chemistry·Rino RagnoPaolo La Colla