Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design.
Diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitors (NNRTIs) have inherent flexibility, helping to maintain activity against a wide range of resistance mutations. Crystal structures were determined with wild-type and K103N HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278). These structures reveal a similar binding mode for TMC125 and TMC278, whether bound to wild-type or K103N RT. Comparison to previously published structures reveals differences in binding modes for TMC125 and differences in protein conformation for TMC278.
Lansdon
Eric B
EB
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, USA. eric.lansdon@gilead.com
Brendza
Katherine M
KM
Hung
Magdeleine
M
Wang
Ruth
R
Mukund
Susmith
S
Jin
Debi
D
Birkus
Gabriel
G
Kutty
Nilima
N
Liu
Xiaohong
X
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D009154:Mutation; D009570:Nitriles / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D011724:Pyridazines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D000068696:Rilpivirine
D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine