Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes

详细信息    查看全文

• 作者：Pavlna ezov ; Jana Pokorn ; Ji Brynda ; Milan Koek ; Petr Cgler ; Martin Lepk ; Jindich Fanfrlk ; Jan ez ; Klra Grantz akov ; Irena Sieglov ; Jaromr Pleek ; Vclav cha ; Bohumr Grner ; Heike Oberwinkler ; Juraj Sedl
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 26, 2009
• 年：2009
• 卷：52
• 期：22
• 页码：7132-7141
• 全文大小：1035K
• 年卷期：v.52,no.22(November 26, 2009)
• ISSN：1520-4804

文摘

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.