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Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes

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journal contribution
posted on 26.11.2009 by Pavlína Řezáčová, Jana Pokorná, Jiří Brynda, Milan Kožíšek, Petr Cígler, Martin Lepšík, Jindřich Fanfrlík, Jan Řezáč, Klára Grantz Šašková, Irena Sieglová, Jaromír Plešek, Václav Šícha, Bohumír Grüner, Heike Oberwinkler, Juraj Sedláček’, Hans-Georg Kräusslich, Pavel Hobza, Vladimír Král, Jan Konvalinka
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 [H2N-(8-(C2H4O)2-1,2-C2B9H10)(1′,2′-C2B9H11)-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.

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