Mimicore Project - Natural and Unnatural Mimetics of Polyfunctional Fragments and their Application in Medicinal Chemistry - The 2,5-dihydroxy-3-methyl-1,4-benzoquinone case

By applying a multivariate similarity search method based on the Principal Component Analysis of databases of fragments defined by bi- and tridimensional molecular descriptors, systematically diverse fragments were identified as potential mimetics of the natural 2,5-dihydroxy-3-methylbenzoquinone (DHMBQ) core occurring in Nature. Three different databases were used, which were derived by manual exclusion of selected classes of molecules from a publicly available database of 13802 commercial fragments complying with the 'rule of three'. Upon computation of more than 300 2D and 3D molecular descriptors, parallel PCA projects were created starting from the three databases, providing very similar models that were described by 9-12 significant components (eigen. > 2.5). Common to all models, in which the third component accounted for 60-65% of the overall variability (Q2(cum) 59-63%), 171 2D and 3D descriptors were found. Using the different ionization forms of DHMBQ as the queries for the similarity search, fragments recurring among the models within the Euclidean distance of 4 units from the queries were selected across the first three components, producing a small library of 93 mimetics belonging to highly diverse chemical types. Within this library, 22 fragments were selected for experiments of binding via Surface Plasmon Resonance (SPR) on two proteins targeted by DHMBQ-containing Natural Products (Xlinked Inhibitor of Apoptosis Protein, XIAP, and Insulin-like Growth Factor Receptor 1, IGF1R), providing 17 new binders for these proteins. Preliminary results from the structure-based elaboration of the binders are presented.