This presentation will focus primarily on applying diverse molecular modeling and structure-informed drug discovery (SIDD) to oncology and infectious diseases (ID) targets. Utilization of rational design along with 'out of the box' hypothesis generation is exemplified for CDK2, CHK1 and NS5B.Oncology targets: Serine and threonine kinases play a pivotal role in signal transduction pathways. Within the kinase family, cyclin-dependent 2 kinase (CDK2) and CHK1 are attractive oncology targets involved in cell cycle regulation. Kinase inhibition in general and CDK2 and CHK1 inhibition in particular have become a major area for oncologic therapeutic involvement. Such efforts have resulted a considerable increase in the number of available high-resolution structures of kinase-inhibitor complexes and therefore, a valuable source of information for computational approaches. Encompassing SIDD approaches that have allowed proactive identification of novel scaffolds and structural motifs to design potent CDK2 (1,2) and CHK1 (3,4) inhibitors will be presented: a) unusual protein-ligand interactions and their isosteric value to design; b) protein flexibility signatures and the impact on novel inhibition approaches and specificity; c) role of solvation in kinase inhibition and selectivity.ID Targets: the HCV nonstructural protein 5B (NS5B) is considered an important target for drug discovery due to its essential function in the replication of viral RNA genome. SIDD work carried out for two series of HCV NS5B inhibitors (5,6) will be described, with special emphasis on the value of identifying novel structural isosteric replacements to maximize �unexepected� structure-informed interactions, protein flexibility and novel sites of binding. References1) Bioorg. Med. Chem. Lett. 2007 Nov 15;17(22):6216-9.2) Fut. Med. Chem. 2009 Nov 12; 1(8):1453-1466.3) Bioorg. Med. Chem. Lett. 2011 Jan 1;21(1):467-70.4) Bioorg. Med. Chem. Lett. 2011 Jan 1;21(1):471-4.5) Bioorg. Med. Chem. Lett. 2010 Apr 1; 20(7):2119-2124.6) Bioorg. Med. Chem. Lett. 2011 Sep 15; 21(18):5336-5341.

Infrequent protein-ligand interactions and protein flexibility on the driver's seat of structure-informed drug discovery

243rd National Meeting (2012)

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