Abstract

The target proteasome has been the focus of drug discovery since the first drug bortezomib was launched in 2003. Many structurally diverse proteasome inhibitors were discovered and even some of them entered the clinical trials. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computeraided drug design (CADD) plays a more and more important role in todays drug discovery. Many CADD technologies were employed in designing various inhibitors of proteasome in the past years. This review gives a global description of the development of computer-aided proteasome inhibitor design by using different commercial or academic software. The binding modes of some structurally novel inhibitors with proteasome were visualized with these new technologies.

Keywords: Proteasome inhibitor, Computer-aided drug design, Rational drug design, biological targets, polyubiquitin chains, constitutive proteasome, drug discovery, N-terminal threonine, nucleophilic attack, amide compounds, biologically evaluated, CH hydrogen and electron system, hydrogen bonds, ubiquitin-proteasome pathway