1c1b
CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH GCA-186
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OverviewOverview
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.
About this StructureAbout this Structure
1C1B is a Protein complex structure of sequences from Human immunodeficiency virus 1 with GCA as ligand. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.
ReferenceReference
Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants., Hopkins AL, Ren J, Tanaka H, Baba M, Okamato M, Stuart DI, Stammers DK, J Med Chem. 1999 Nov 4;42(22):4500-5. PMID:10579814
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