Design of HIV protease inhibitors based on inorganic polyhedral metallacarboranes

J Med Chem. 2009 Nov 26;52(22):7132-41. doi: 10.1021/jm9011388.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Boron Compounds / chemical synthesis
  • Boron Compounds / chemistry*
  • Boron Compounds / metabolism
  • Boron Compounds / pharmacology*
  • Carbon / chemistry*
  • Cobalt / chemistry*
  • Crystallography, X-Ray
  • Drug Design*
  • Electrons
  • HIV Protease / chemistry
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / metabolism
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • Models, Molecular
  • Molecular Conformation

Substances

  • Boron Compounds
  • HIV Protease Inhibitors
  • Cobalt
  • Carbon
  • HIV Protease

Associated data

  • PDB/3I8W