title: Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants.
abstract: Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.
authors.affiliation: Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: A L
authors.initials: AL
authors.lastname: Hopkins
authors.forename: J
authors.initials: J
authors.lastname: Ren
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: M
authors.initials: M
authors.lastname: Okamato
authors.forename: D I
authors.initials: DI
authors.lastname: Stuart
authors.forename: D K
authors.initials: DK
authors.lastname: Stammers
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C510377:6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil; D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; C083858:emivirine