Abstract
Proteasome emerged as an important target in recent pharmacological research due to its pivotal role in degrading proteins in the cytoplasm and nucleus of eukaryotic cells, regulating a wide variety of cellular pathways, including cell growth and proliferation, apoptosis, DNA repair, transcription, immune response, and signaling processes. The last two decades witnessed intensive efforts to discover 20S proteasome inhibitors with significant chemical diversity and efficacy. To date, the US FDA approved to market three proteasome inhibitors: bortezomib, carfilzomib, and ixazomib. However new, safer and more efficient drugs are still required. Computer-aided drug discovery has long being used in drug discovery campaigns targeting the human proteasome. The aim of this review is to illustrate selected in silico methods like homology modeling, molecular docking, pharmacophore modeling, virtual screening, and combined methods that have been used in proteasome inhibitors discovery. Applications of these methods to proteasome inhibitors discovery will also be presented and discussed to raise improvements in this particular field.
Highlights
The results showed that the reaction pathway has three steps: first, a direct proton transfer occurs from the threonine 1 (Thr1)-Oγ to the Thr1-Nz to activate the Thr1-Oγ; in the second step the negatively charged Thr1-Oγ attacks the olefin carbon of
The application of computer-aided drug design methodologies was crucial to assist in the efforts to improve and speed up the discovery of compounds that show a significant inhibitory activity against human proteasome
In this overview the application of several in silico methodologies, such as homology modeling, pharmacophore generation, molecular docking, virtual screening, quantum mechanics, and molecular dynamics to identify and optimize new proteasome inhibitors as well as to give invaluable insights on the key interactions and catalytic mechanisms involved in proteasome inhibition, was revised
Summary
The existence of a highly regulated turnover of cellular proteins contributes to cellular homeostasis, a delicate balance between protein synthesis and protein degradation mechanisms [1]. In this way, denatured proteins, damaged proteins (due to, for example, oxidative stress) or proteins that are no longer needed, are recognized and removed through proteolytic degradation, catalyzed by proteases that cleave peptide bonds [2,3,4,5,6]. Proteins modified with an ubiquitin chain bind to ubiquitin receptors that link them to the 26S proteasome, which degrades ubiquitinated proteins and recycles the Molecules 2016, 21, 927; doi:10.3390/molecules21070927 www.mdpi.com/journal/molecules
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