Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
Das
Kalyan
K
Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
Clark
Arthur D
AD
Lewi
Paul J
PJ
Heeres
Jan
J
De Jonge
Marc R
MR
Koymans
Lucien M H
LM
Vinkers
H Maarten
HM
Daeyaert
Frederik
F
Ludovici
Donald W
DW
Kukla
Michael J
MJ
De Corte
Bart
B
Kavash
Robert W
RW
Ho
Chih Y
CY
Ye
Hong
H
Lichtenstein
Mark A
MA
Andries
Koen
K
Pauwels
Rudi
R
De Béthune
Marie-Pierre
MP
Boyer
Paul L
PL
Clark
Patrick
P
Hughes
Stephen H
SH
Janssen
Paul A J
PA
Arnold
Eddy
E
D019380:Anti-HIV Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D009570:Nitriles; D011487:Protein Conformation; D011724:Pyridazines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*
D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D054303:HIV Reverse Transcriptase; C481671:Dapivirine