Drug discovery in the kinase inhibitory field using the Nested Chemical Library technology.
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.
Kéri
György
G
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
Székelyhidi
Zsolt
Z
Bánhegyi
Péter
P
Varga
Zoltán
Z
Hegymegi-Barakonyi
Bálint
B
Szántai-Kis
Csaba
C
Hafenbradl
Doris
D
Klebl
Bert
B
Muller
Gerhard
G
Ullrich
Axel
A
Erös
Dániel
D
Horváth
Zoltán
Z
Greff
Zoltán
Z
Marosfalvi
Jenö
J
Pató
János
J
Szabadkai
István
I
Szilágyi
Ildikó
I
Szegedi
Zsolt
Z
Varga
István
I
Wáczek
Frigyes
F
Orfi
László
L
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*
D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors