title: 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.
abstract: 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.
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Clark
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lewi
authors.forename: Jan
authors.initials: J
authors.lastname: Heeres
authors.forename: Marc R
authors.initials: MR
authors.lastname: De Jonge
authors.forename: Lucien M H
authors.initials: LM
authors.lastname: Koymans
authors.forename: H Maarten
authors.initials: HM
authors.lastname: Vinkers
authors.forename: Frederik
authors.initials: F
authors.lastname: Daeyaert
authors.forename: Donald W
authors.initials: DW
authors.lastname: Ludovici
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kukla
authors.forename: Bart
authors.initials: B
authors.lastname: De Corte
authors.forename: Robert W
authors.initials: RW
authors.lastname: Kavash
authors.forename: Chih Y
authors.initials: CY
authors.lastname: Ho
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lichtenstein
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Rudi
authors.initials: R
authors.lastname: Pauwels
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: De Béthune
authors.forename: Paul L
authors.initials: PL
authors.lastname: Boyer
authors.forename: Patrick
authors.initials: P
authors.lastname: Clark
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Janssen
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
mesh_terms: 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*
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D054303:HIV Reverse Transcriptase; C481671:Dapivirine