1JLQ

CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH 739W94

Summary for 1JLQ

• Entry DOI: 10.2210/pdb1jlq/pdb
• Related: 1C0T 1C0U 1C1B 1C1C 1DTQ 1DTT 1EP4 1FK9 1FKO 1FKP 1JKH 1JLA 1JLB 1JLC 1JLE 1JLF 1JLG 1KLM 1REV 1RT1 1RT2 1RT3 1RT4 1RT5 1RT6 1RT7 1RTH 1RTI 1RTJ 1VRT 1VRU
• Descriptor: HIV-1 RT, A-CHAIN, HIV-1 RT, B-CHAIN, 2-AMINO-6-(3,5-DIMETHYLPHENYL)SULFONYLBENZONITRILE (3 entities in total)
• Functional Keywords: hiv-1 reverse transcriptase, aids, non-nucleoside inhibitor, 739w94, drug design, transferase
• Biological source: HIV-1 M:B_HXB2R; More
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor . Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04585 P04585
• Total number of polymer chains: 2
• Total formula weight: 116280.35

Authors

Ren, J.,Stuart, D.I.,Stammers, D.K. (deposition date: 2001-07-16, release date: 2001-08-22, Last modification date: 2022-12-21)

Primary citation

Chan, J.H.,Hong, J.S.,Hunter III, R.N.,Orr, G.F.,Cowan, J.R.,Sherman, D.B.,Sparks, S.M.,Reitter, B.E.,Andrews III., C.W.,Hazen, R.J.,St Clair, M.,Boone, L.R.,Ferris, R.G.,Creech, K.L.,Roberts, G.B.,Short, S.A.,Weaver, K.,Ott, R.J.,Ren, J.,Hopkins, A.,Stuart, D.I.,Stammers, D.K.
2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.
J.Med.Chem., 44:1866-1882, 2001

PubMed Abstract: 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.

PubMed: 11384233
DOI: 10.1021/jm0004906

Experimental method

X-RAY DIFFRACTION (3 Å)