Activity of diverse chalcones against several targets: statistical analysis of a high-throughput virtual screen of a custom chalcone library

Chalcone family molecules are well known to have therapeutic proprieties (anti-inflammatory, anti-microbial or anti-cancer, etc). However the mechanism of action in some cases is not well known. A virtual library of this family of compounds was constructed using custom scripts, based on the aldol condensation, and this library was modified further to analogues by expansion of the α,β-unsaturated ketone linker. Acetophenone and benzaldehyde derivatives which are available and purchasable were used as a base to design the chalcone virtual library. 8063 chalcones were constructed and geometrically optimized with Gaussian 09. Their physicochemical characteristics linked to the Lipinski rules were analyzed with Knime and CDK. The entire library was after docked against several targets including HIV-1 integrase, MRSA pyruvate kinase, HSP90, COX-1, COX-2, ALR2, MAOA, MAOB, acetylcholinesterase, butyrylcholinesterase and PLA2. With the exception of MAOA, which does not have a crystal structure ligand, all dockings were validated by redocking the original ligand provided by the literature. These targets are known in the literature to be inhibited by chalcone-derivatives. However, specificity of the particular known chalcone inhibitors to the particular targets is not known. To this end the performance of the generated chalcone library against the list of targets was of interest. The binding energy of ligand-protein complexes was generally good across the library. Statistical analysis including principal component analysis and hierarchical clustering analysis were made in order to investigate for any physical/chemical characteristics which might explain what chalcone features affect the binding energy of the ligand-protein complexes. The spherical polar coordinates defining the orientation of the binding poses were also calculated and used in the statistical analysis. The statistical analysis has allowed us to hypothesize the importance of these radial distances and the polar angles of key atoms in the chalcones in binding to the pyruvate kinase crystal structure. This was validated by the docking of another small library of compound models in which the α,β-unsaturated ketone chain of the chalcone was replaced by incrementally longer conjugated chains. Further studies on the chalcones themselves reveal rotameric systems in both cis and trans-configurations (which may impact binding), and also studied was the effect of Topliss-based modification and its impact of binding to HSP90. Molecular dynamics confirmed good binding of identified chalcone hits