Drug Discovery in the Kinase Inhibitory Field Using the Nested Chemical Library™ Technology
Gÿorgý Kéri, Zsolt Székelyhidi, Péter Bánhegyi, Zoltán V. Varga, Bálint Hegymegi-Barakonyi, Csaba Szántai-Kis, Doris Hafenbradl, Bert Klebl, Gerhard Müller, Axel Ullrich, Dániel Erös, Zoltán Horváth, Zoltán Greff, Marosfalvi Jeno, János Pató, István Szabadkai, Ildikó Szilágyi, Zsolt Szegedi, István Varga, Frigyes Wáczek · Assay and Drug Development Technologies · 2005
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.