Design of HIV protease inhibitors based on inorganic polyhedral metallacarboranes.
HIV protease (HIV PR) is a primary target for anti-HIV drug design. We have previously identified and characterized substituted metallacarboranes as a new class of HIV protease inhibitors. In a structure-guided drug design effort, we connected the two cobalt bis(dicarbollide) clusters with a linker to substituted ammonium group and obtained a set of compounds based on a lead formula [H(2)N-(8-(C(2)H(4)O)(2)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co)(2)]Na. We explored inhibition properties of these compounds with various substitutions, determined the HIV PR:inhibitor crystal structure, and computationally explored the conformational space of the linker. Our results prove the capacity of linker-substituted dual-cage cobalt bis(dicarbollides) as lead compounds for design of more potent inhibitors of HIV PR.
Rezácová
Pavlína
P
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Gilead Sciences and IOCB Research Center, Flemingovo nam. 2, 16610 Praha 6, Czech Republic. rezacova@uochb.cas.cz
Pokorná
Jana
J
Brynda
Jirí
J
Kozísek
Milan
M
Cígler
Petr
P
Lepsík
Martin
M
Fanfrlík
Jindrich
J
Rezác
Jan
J
Grantz Sasková
Klára
K
Sieglová
Irena
I
Plesek
Jaromír
J
Sícha
Václav
V
Grüner
Bohumír
B
Oberwinkler
Heike
H
Sedlácek'
Juraj
J
Kräusslich
Hans-Georg
HG
Hobza
Pavel
P
Král
Vladimír
V
Konvalinka
Jan
J
D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002244:Carbon / Q000737:chemistry*; D003035:Cobalt / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004583:Electrons; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation
D001896:Boron Compounds; D017320:HIV Protease Inhibitors; D003035:Cobalt; D002244:Carbon; D016333:HIV Protease