Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes
| Autor: | Jan Konvalinka, Jana Pokorná, Bohumír Grüner, Jaromír Plešek, Pavlina Rezacova, Heike Oberwinkler, Klára Grantz Šašková, Václav Šícha, Petr Cigler, Vladimír Král, Pavel Hobza, Hans-Georg Kräusslich, Martin Lepšík, Jindrich Fanfrlík, Juraj Sedlacek, Irena Sieglová, Milan Kozisek, Jan Rezac, Jiri Brynda |
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| Rok vydání: | 2009 |
| Předmět: |
Boron Compounds
Models Molecular Molecular model Stereochemistry medicine.medical_treatment Molecular Conformation Electrons Crystal structure Crystallography X-Ray HIV Protease Drug Discovery medicine HIV Protease Inhibitor Protease inhibitor (pharmacology) chemistry.chemical_classification Protease biology Chemistry Cobalt HIV Protease Inhibitors Carbon Enzyme Enzyme inhibitor Drug Design HIV-1 biology.protein Molecular Medicine Linker |
| Zdroj: | Journal of Medicinal Chemistry. 52:7132-7141 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm9011388 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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