title: Pharmacophore modeling technique applied for the discovery of proteasome inhibitors.
abstract: BACKGROUND
  The 26S proteasome has many important roles in the biological functions of the cells, and proteasome inhibitors have multiple and complex activities on cells. These compounds can be natural or synthesized. Most synthetic derivatives have been rationally designed, synthesized and optimized to obtain the best selectivity and increase the activity. The design of chemical entities with desired molecular identification, which plays an important role in biological systems, is provided by pharmacophore modeling. Indeed, pharmacophore models can be established either in a ligand-based manner or in a receptor-based manner.
  
  
  METHODS
  The authors discuss the application of pharmacophore modeling techniques to proteasome inhibitors development. Furthermore, the article reviews the classification of the currently discovered proteasome inhibitors where the principal mechanism of action and clinical application are represented.
  
  
  CONCLUSIONS
  In the era of new drug development, database of compounds should be thoroughly evaluated with a combination of methods that consider both pharmacophore- and ligand-based virtual screening. The concept of pharmacophore helps to discover new active compounds and to evaluate their activity. The nature of proteasome inhibitor pharmacophore affects the secondary active-site specificity; indeed, increasing specificity decreases the cytotoxicity of the proteasome inhibitors. It is hypothesized that the balanced simultaneous modulation of a few druggable targets may have superior efficacy and fewer side effects than single-target or combination therapies for the treatment of human cancers. The discovery of new compounds should aim to find more active compounds that improve the compliance of patients.
authors.affiliation: University of Torino, Myeloma Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Division of Hematology , Torino , Italy appalumbo@yahoo.com ; pautasso.chiara@gmail.com.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pautasso
authors.forename: Rossella
authors.initials: R
authors.lastname: Troia
authors.forename: Mariella
authors.initials: M
authors.lastname: Genuardi
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: myeloma; pharmacophore; proteasome inhibitors