Esnouf R M, Stuart D I, De Clercq E, Schwartz E, Balzarini J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Biochem Biophys Res Commun. 1997 May 19;234(2):458-64. doi: 10.1006/bbrc.1997.6552.
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.
（硫代）羧酰苯胺衍生物是HIV-1逆转录酶（RT）的强效和选择性抑制剂，具有良好的抗病毒活性谱。为了更好地理解它们的作用模式，并为进一步改进提供结构基础，基于RT与9-氯-TIBO复合的X射线结构，构建了与四种（硫代）羧酰苯胺抑制剂（UC781、UC10、UC38和UC84）复合的RT模型。在这些模型中，蛋白质构象与RT-TIBO复合物相似，并且复合物通过抑制剂与Lys101主链氧之间的氢键而稳定。重要的疏水相互作用包括与Leu100、Val106、Val179、Tyr188、Phe227、Leu234和His235的相互作用。硫代羧酰苯胺UC781和UC10也与Trp229形成重要的疏水相互作用。这些模型与抑制剂的相对抗病毒效力和观察到的耐药性数据一致。它们进一步预测，Phe227、Trp229或Leu234的突变可能导致耐药性。由于未观察到这些情况，提示这些残基在活性酶中具有一些限制性的结构或功能作用。
