| Autor: |
Kéri, György, Székelyhidi, Zsolt, Bánhegyi, Péter, Varga, Zoltán, Hegymegi-Barakonyi, Bálint, Szántai-Kis, Csaba, Hafenbradl, Doris, Klebl, Bert, Muller, Gerhard, Ullrich, Axel, Erös, Dániel, Horváth, Zoltán, Greff, Zoltán, Marosfalvi, Jenö, Pató, János, Szabadkai, István, Szilágyi, Ildikó, Szegedi, Zsolt, Varga, István, Wáczek, Frigyes, Örfi, László |
| Zdroj: |
Assay and Drug Development Technologies; October 2005, Vol. 3 Issue: 5 p543-551, 9p |
| Abstrakt: |
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, threedimensional 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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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