title: Binding modes of two novel non-nucleoside reverse transcriptase inhibitors, YM-215389 and YM-228855, to HIV type-1 reverse transcriptase.
abstract: BACKGROUND
  YM-215389 and YM-228855 are thiazolidenebenzenesulfonamide (TBS) derivatives and novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) that inhibit not only wild-type, but also the K103N- and Y181C-substituted reverse transcriptase (RT) of HIV type-1 (HIV-1).
  
  
  METHODS
  To characterize the binding modes of the TBS derivatives in detail, the anti-HIV-1 activities of YM-215389 and YM-228855 against various NNRTI-resistant clones were examined. Docking studies with HIV-1 RT were also performed.
  
  
  RESULTS
  YM-215389, which effectively inhibits various NNRTI-resistant clones, interacted with L100, K103, V106 and Y318 through the benzene ring and with E138, V179, Y181, Y188 and W229 through the thiazole ring. A single amino acid substitution confers only moderate resistance to YM-215389; indeed, four amino acid substitutions (V106L, V108I, E138K and L214F) were necessary for high-level resistance. Although the activity of YM-228855, a derivative of YM-215389 that has two bulky and rigid cyano-moieties on the benzene ring, was 10x more potent against HIV-1 than YM-215389, its anti-HIV-1 activity was readily reduced with single substitutions as with Y181I and K103N.
  
  
  CONCLUSIONS
  These results provide structural information for optimizing the TBS derivatives in an attempt to construct ideal NNRTIs that maintain anti-HIV-1 activity to various HIV-1 variants.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan. ekodama@virus.kyoto-u.ac.jp
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kodama
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Masuda
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamomoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujii
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ohgami
authors.forename: Shunji
authors.initials: S
authors.lastname: Kageyama
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hatta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Sudo
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; C533678:YM 215389; C533679:YM 228855; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase