Drug discovery in the kinase inhibitory field using the nested chemical library™ technology

György Kéri, Zsolt Székelyhidi, Péter Bánhegyi, Zoltán Varga, Bálint Hegymegi-Barakonyi, Csaba Szántai-Kis, Doris Hafenbradl, Bert Klebl, Gerhard Muller, Axel Ullrich, Dániel Erös, Zoltán Horváth, Zoltán Greff, Jenö Marosfalvi, János Pató, István Szabadkai, Ildikó Szilágyi, Zsolt Szegedi, István Varga, Frigyes WáczekLászló Örfi

Research output: Review article

27 Citations (Scopus)

Abstract

Kinase inhibitors are at the forefront of modern drug research, where mostly three technologies are used for hit-and-lead finding: high throughput screening of random libraries, three-dimensional structure-based drug design based on X-ray data, and focused libraries around limited number of new cores. Our novel Nested Chemical Library™ (NCL) (Vichem Chemie Research Ltd., Budapest, Hungary) technology is based on a knowledge base approach, where focused libraries around selected cores are used to generate pharmacophore models. NCL was designed on the platform of a diverse kinase inhibitory library organized around 97 core structures. We have established a unique, proprietary kinase inhibitory chemistry around these core structures with small focused sublibraries around each core. All the compounds in our NCL library are stored in a big unified Structured Query Language database along with their measured and calculated physicochemical and ADME/toxicity (ADMET) properties, together with thousands of molecular descriptors calculated for each compound. Biochemical kinase inhibitory assays on selected, cloned kinase enzymes for a few hundred NCL compound sets can provide sufficient biological data for rational computerized design of new analogues, based on our pharmacophore model-generating 3DNET4W™ QSPAR (quantitative structure-property/activity relationships) approach. Using this pharmacophore modeling approach and the ADMET filters, we can preselect synthesizable compounds for hit-and-lead optimization. Starting from this point and integrating the information from QSPAR, high-quality leads can be generated within a small number of optimization cycles. Applying NCL technology we have developed lead compounds for several validated kinase targets.

Original languageEnglish
Pages (from-to)543-551
Number of pages9
JournalAssay and Drug Development Technologies
Volume3
Issue number5
DOIs
Publication statusPublished - okt. 1 2005

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Kéri, G., Székelyhidi, Z., Bánhegyi, P., Varga, Z., Hegymegi-Barakonyi, B., Szántai-Kis, C., Hafenbradl, D., Klebl, B., Muller, G., Ullrich, A., Erös, D., Horváth, Z., Greff, Z., Marosfalvi, J., Pató, J., Szabadkai, I., Szilágyi, I., Szegedi, Z., Varga, I., ... Örfi, L. (2005). Drug discovery in the kinase inhibitory field using the nested chemical library™ technology. Assay and Drug Development Technologies, 3(5), 543-551. https://doi.org/10.1089/adt.2005.3.543