Depsides and depsidones as inhibitors of HIV-1 integrase: discovery of novel inhibitors through 3D database searching.
Seventeen lichen acids comprising despides, depsidones, and their synthetic derivatives have been examined for their inhibitory activity against HIV-1 integrase, and two pharmacophores associated with inhibition of this enzyme have been identified. A search of the NCI 3D database of approximately 200,000 structures yielded some 800 compounds which contain one or the other pharmacophore. Forty-two of these compounds were assayed for HIV-1 integrase inhibition, and of these, 27 had inhibitory IC50 values of less than 100 microM; 15 were below 50 microM. Several of these compounds were also examined for their activity against HIV-2 integrase and mammalian topoisomerase I.
Neamati
N
N
Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland 20892-4255, USA.
Hong
H
H
Mazumder
A
A
Wang
S
S
Sunder
S
S
Nicklaus
M C
MC
Milne
G W
GW
Proksa
B
B
Pommier
Y
Y
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002460:Cell Line; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D016208:Databases, Factual; D053630:Depsides; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D015498:HIV-2 / Q000201:enzymology; D062385:Hydroxybenzoates / Q000737:chemistry* / Q000494:pharmacology*; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008011:Lichens / Q000737:chemistry; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D019380:Anti-HIV Agents; D053630:Depsides; D019428:HIV Integrase Inhibitors; D062385:Hydroxybenzoates; D007783:Lactones; D009838:Oligodeoxyribonucleotides; D059004:Topoisomerase I Inhibitors; C000875:depsidone; D019427:HIV Integrase; D004264:DNA Topoisomerases, Type I