Structure-aided design of novel inhibitors of HIV protease based on a benzodiazepine scaffold.
HIV protease is a primary target for the design of virostatics. Screening of libraries of non-peptide low molecular weight compounds led to the identification of several new compounds that inhibit HIV PR in the low micromolar range. X-ray structure of the complex of one of them, a dibenzo[b,e][1,4]diazepinone derivative, showed that two molecules of the inhibitor bind to the PR active site. Covalent linkage of two molecules of such a compound by a two-carbon linker led to a decrease of the inhibition constant of the resulting compound by 3 orders of magnitude. Molecular modeling shows that these dimeric inhibitors form two crucial hydrogen bonds to the catalytic aspartates that are responsible for their improved activity compared to the monomeric parental building blocks. Dibenzo[b,e][1,4]diazepinone analogues might represent a potential new class of HIV PIs.
Institute of Organic Chemistry and Biochemistry, Gilead Sciences and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10, Prague 6, Czech Republic.
Jiří
J
Schimer
Petr
P
Cígler
Jan
J
Veselý
Klára
K
Grantz Šašková
Martin
M
Lepšík
Jiří
J
Brynda
Pavlína
P
Rezáčová
Milan
M
Kožíšek
Ivana
I
Císařová
Heike
H
Oberwinkler
Hans-Georg
HG
Kraeusslich
Jan
J
Konvalinka
D001569:Benzodiazepines / Q000737:chemistry*; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D010446:Peptide Fragments; D001569:Benzodiazepines; D016333:HIV Protease