3T1A

Crystal Structure of HIV-1 Reverse Transcriptase (K103N mutant) in Complex with Inhibitor M05

3T1A の概要

• エントリーDOI: 10.2210/pdb3t1a/pdb
• 関連するPDBエントリー: 3T19 3TAM
• 分子名称: Reverse Transcriptase, 1-(2,5-dichloro-3-{[5-chloro-1-(2H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-1H-benzotriazol-4-yl]oxy}phenyl)methanamine (3 entities in total)
• 機能のキーワード: hiv-1 reverse transcriptase, non-nucleoside inhibition, nucleotidyltranferase, hiv-1, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: HIV-1 M:B_HXB2R (HIV-1)
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P04585
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 130235.21

構造登録者

Yan, Y.,Reid, J. (登録日: 2011-07-21, 公開日: 2011-10-26, 最終更新日: 2024-03-13)

主引用文献

Gomez, R.,Jolly, S.J.,Williams, T.,Vacca, J.P.,Torrent, M.,McGaughey, G.,Lai, M.T.,Felock, P.,Munshi, V.,Distefano, D.,Flynn, J.,Miller, M.,Yan, Y.,Reid, J.,Sanchez, R.,Liang, Y.,Paton, B.,Wan, B.L.,Anthony, N.
Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptase.
J.Med.Chem., 54:7920-7933, 2011

PubMed Abstract: Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.

PubMed: 21985673
DOI: 10.1021/jm2010173

実験手法

X-RAY DIFFRACTION (2.4 Å)