title: Design of HIV protease inhibitors based on inorganic polyhedral metallacarboranes.
abstract: 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.
authors.affiliation: 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
authors.forename: Pavlína
authors.initials: P
authors.lastname: Rezácová
authors.forename: Jana
authors.initials: J
authors.lastname: Pokorná
authors.forename: Jirí
authors.initials: J
authors.lastname: Brynda
authors.forename: Milan
authors.initials: M
authors.lastname: Kozísek
authors.forename: Petr
authors.initials: P
authors.lastname: Cígler
authors.forename: Martin
authors.initials: M
authors.lastname: Lepsík
authors.forename: Jindrich
authors.initials: J
authors.lastname: Fanfrlík
authors.forename: Jan
authors.initials: J
authors.lastname: Rezác
authors.forename: Klára
authors.initials: K
authors.lastname: Grantz Sasková
authors.forename: Irena
authors.initials: I
authors.lastname: Sieglová
authors.forename: Jaromír
authors.initials: J
authors.lastname: Plesek
authors.forename: Václav
authors.initials: V
authors.lastname: Sícha
authors.forename: Bohumír
authors.initials: B
authors.lastname: Grüner
authors.forename: Heike
authors.initials: H
authors.lastname: Oberwinkler
authors.forename: Juraj
authors.initials: J
authors.lastname: Sedlácek'
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kräusslich
authors.forename: Pavel
authors.initials: P
authors.lastname: Hobza
authors.forename: Vladimír
authors.initials: V
authors.lastname: Král
authors.forename: Jan
authors.initials: J
authors.lastname: Konvalinka
mesh_terms: 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
chemical_list: D001896:Boron Compounds; D017320:HIV Protease Inhibitors; D003035:Cobalt; D002244:Carbon; D016333:HIV Protease