title: Computational Approaches for the Discovery of Human Proteasome Inhibitors: An Overview.
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.
authors.affiliation: iMed.ULisboa, Research Institute for Medicines, Faculdade de Farm&#225;cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. rpaguedes@gmail.com.
authors.forename: Romina A
authors.initials: RA
authors.lastname: Guedes
authors.affiliation: iMed.ULisboa, Research Institute for Medicines, Faculdade de Farm&#225;cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. patriciafaserra@gmail.com.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Serra
authors.affiliation: Laborat&#243;rio de Qu&#237;mica Farmac&#234;utica, Faculdade de Farm&#225;cia da Universidade de Coimbra, P&#243;lo das Ci&#234;ncias da Sa&#250;de-Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. salvador@ci.uc.pt.|Center for Neurosciences and Cell Biology, Universidade de Coimbra, Rua Larga-Faculdade de Medicina, P&#243;lo I, 3004-504 Coimbra, Portugal. salvador@ci.uc.pt.
authors.forename: Jorge A R
authors.initials: JA
authors.lastname: Salvador
authors.affiliation: iMed.ULisboa, Research Institute for Medicines, Faculdade de Farm&#225;cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. rguedes@ff.ulisboa.pt.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: cancer; computer-aided drug design; molecular docking; pharmacophore model; proteasome inhibitors; virtual screening