A Rational Approach Towards the Identification of Ligands Directed to Single and Multiple Targets of Systems Biology Diseases (Progetto STM 2009: Statistical Molecular Design of an Embelin-Inspired Library of XIAP-Inhibitors) (Rapporti progetti di ricerca)

Type

• Prodotto della ricerca (Classe)
• Rapporti progetti di ricerca (Classe)

Label

• A Rational Approach Towards the Identification of Ligands Directed to Single and Multiple Targets of Systems Biology Diseases (Progetto STM 2009: Statistical Molecular Design of an Embelin-Inspired Library of XIAP-Inhibitors) (Rapporti progetti di ricerca) (literal)

Anno

• 2010-01-01T00:00:00+01:00 (literal)

Alternative label

• Luciana Auzzas (2010)
  A Rational Approach Towards the Identification of Ligands Directed to Single and Multiple Targets of Systems Biology Diseases (Progetto STM 2009: Statistical Molecular Design of an Embelin-Inspired Library of XIAP-Inhibitors)
  
  (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

• Luciana Auzzas (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#note

• Programma STM2009, relazione finale (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#supporto

• Altro (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni

• Istituto di Chimica Biomolecolare del CNR - Sede di Sassari (literal)

Titolo

• A Rational Approach Towards the Identification of Ligands Directed to Single and Multiple Targets of Systems Biology Diseases (Progetto STM 2009: Statistical Molecular Design of an Embelin-Inspired Library of XIAP-Inhibitors) (literal)

Abstract

• A re-evaluation of the modern principles of Fragment-Based Design is presented in this investigation, which opens new perspectives to the design of multitargeted ligands as biological tools and potential leads for Systems Biology-based diseases, with a special emphasis on cancer. The preliminary results of the methodology are here described, which integrates Chemometrics and Molecular Modeling with biostructural information available from naturally occurring, promiscuously active products, in an effort to anticipate the identification of multitargeted proapoptotic modulators in early and less expensive stages of the drug design. As a starting multiple-active chemotype, a dihydroxyquinone-based naturally occurring fragment was selected. This choice was driven by the intrinsic promiscuity of a wide range of natural quinone-based compounds and strictly related analogues thereof, as well as by the availability of detailed biostructural information pertaining their mechanism of action on phylogenetically related and unrelated proteins. In order to expand the chemical opportunities, isofunctional but structurally diverse chemotypes were selected by similarity search methods against a database of fragments, basing the search on a combination of Principal Component Analysis, Hierarchical Cluster Analysis and Tanimoto coefficient methods. An 'ad-hoc' database of quinone-based analogues were designed biased against synthetic feasibility, drug-likeliness, and biostructural information concerning interactions of quinone-based Natural Products with XIAP and kinases. This database was merged to a pre-compiled database of 13,098 commercial fragments complying with the 'Rule of Three', and 328 molecular descriptors were calculated for each entry. Following the application of the similarity search methods, a discrete library of 66 diverse fragments were selected, which are under investigation by Surface Plasmon Resonance on Biacore against a panel of apoptosis modulator proteins including XIAP (X-Chromosome-linked Inhibitor of Apoptosis Protein), a Serine-Threonin Kinase (B-Raf), Receptor Tyrosine Kinases (VEGF-2, EGFR, HER2, IGF1R), and PI3 kinases (p110alpha-p110gamma, mTOR). A preliminary virtual screening of a small sub-collection of fragments was preformed on XIAP, and directed the choice of a few diverse fragments and their Structure-Based synthetic elaboration as potential non-quinone inhibitors of XIAP. In silico pre-validation of the library on the protein kinase set is in progress. From this investigation, a direct comparison of the different similarity methods selected in this study will be possible, which might disclose novel applications of Principal Component Analysis in Fragment-Based Design of single- and multitargeted ligands. (literal)

Prodotto di

• Scienze chimiche e medicinali dedicate al design di modelli innovativi di ricognizione molecolare: applicazioni per lo sviluppo di metodi e protocolli computazionali (PM.P07.008.002) (Modulo)
• Institute of biomolecular chemistry (ICB) (Istituto)

Autore CNR

• LUCIANA AUZZAS (Persona)

Incoming links:

Autore CNR di

• LUCIANA AUZZAS (Persona)

Prodotto

• Institute of biomolecular chemistry (ICB) (Istituto)
• Scienze chimiche e medicinali dedicate al design di modelli innovativi di ricognizione molecolare: applicazioni per lo sviluppo di metodi e protocolli computazionali (PM.P07.008.002) (Modulo)