1jlq
From Proteopedia
|
CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH 739W94
Overview
A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active, against HIV-1. Structural modifications led to the sulfoxides (2) and, sulfones (3). The sulfoxides generally showed antiviral activity against, HIV-1 similar to that of 1. The sulfones, however, were the most potent, series of analogues, a number having activity against HIV-1 in the, nanomolar range. Structural-activity relationship (SAR) studies suggested, that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral, activities were manifested by compounds where both meta groups in the, arylsulfonyl moiety were substituted and one of the substituents was a, methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y, having IC50 values against HIV-1 in the low nanomolar range. When gauged, for their broad-spectrum antiviral activity against key non-nucleoside, reverse transcriptase inhibitor (NNRTI) related mutants, all the, di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee, generally showed single-digit nanomolar activity against the V106A and, P236L strains and submicromolar to low nanomolar activity against strains, E138K, V108I, and Y188C. However, they showed a lack of activity against, the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal, structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase, showed an overlap in the binding domain when compared with the complex of, nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for, the rationalization of SAR data and potencies of the compounds against the, mutants.
About this Structure
1JLQ is a Protein complex structure of sequences from Human immunodeficiency virus type 1 (isolate hxb2) with SBN as ligand. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.
Reference
2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1., Chan JH, Hong JS, Hunter RN 3rd, Orr GF, Cowan JR, Sherman DB, Sparks SM, Reitter BE, Andrews CW 3rd, Hazen RJ, St Clair M, Boone LR, Ferris RG, Creech KL, Roberts GB, Short SA, Weaver K, Ott RJ, Ren J, Hopkins A, Stuart DI, Stammers DK, J Med Chem. 2001 Jun 7;44(12):1866-82. PMID:11384233
Page seeded by OCA on Thu Nov 8 14:13:29 2007
