title: Drug discovery in the kinase inhibitory field using the Nested Chemical Library technology.
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.
authors.affiliation: Peptide Biochemistry Research Group of Hungarian Academy of Sciences in Department of Medicinal Chemistry and Pathobiochemistry and Rational Drug Design Laboratory Cooperative Research Center, Semmelweis University, Budapest, Hungary. keri@vichem.hu
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Székelyhidi
authors.forename: Péter
authors.initials: P
authors.lastname: Bánhegyi
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Varga
authors.forename: Bálint
authors.initials: B
authors.lastname: Hegymegi-Barakonyi
authors.forename: Csaba
authors.initials: C
authors.lastname: Szántai-Kis
authors.forename: Doris
authors.initials: D
authors.lastname: Hafenbradl
authors.forename: Bert
authors.initials: B
authors.lastname: Klebl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Muller
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.forename: Dániel
authors.initials: D
authors.lastname: Erös
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Horváth
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Greff
authors.forename: Jenö
authors.initials: J
authors.lastname: Marosfalvi
authors.forename: János
authors.initials: J
authors.lastname: Pató
authors.forename: István
authors.initials: I
authors.lastname: Szabadkai
authors.forename: Ildikó
authors.initials: I
authors.lastname: Szilágyi
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szegedi
authors.forename: István
authors.initials: I
authors.lastname: Varga
authors.forename: Frigyes
authors.initials: F
authors.lastname: Wáczek
authors.forename: László
authors.initials: L
authors.lastname: Orfi
mesh_terms: D000465:Algorithms; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D016208:Databases, Factual; D015195:Drug Design; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors