Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 22, Pages 7132-7141Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm9011388
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Funding
- European Commission [LSHP-CT-2007-037693]
- Academy of Sciences of the Czech Republic [AV0Z50520514, AV0Z40320502, AV0Z0550506]
- Grant Agency of the Academy of Sciences of the Czech Republic [IAAX00320901]
- Ministry of Education of the Czech Republic [LC512, LC523]
- Praemium Academiae
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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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