R drugs vs. metabolites (p_DM), drugs vs. overlapping compounds (p_DO), and metabolites vs. overlapping compounds (p_MO) by Kolmogorov mirnov test.Frontiers in Molecular Biosciences | www.frontiersin.orgSeptember 2015 | Volume 2 | ArticleKorkuc and WaltherCompound-protein interactionsFIGURE two | Logarithmic promiscuity Resolvin D3 Technical Information propensity ratios of all compounds (bars) and person compound classes (lines) for diverse physicochemical properties. Constructive propensity values (red colour gradient) denote that a provided home interval is characteristic for promiscuous compounds. Damaging values (blue colour gradient) show that a property interval is biased in favor of selective compounds, which have only a single or two target pockets. Differently colored lines and connected error bars correspond to drugs (red), metabolites (green), and overlapping compounds (blue). Error bars denote the estimated typical error with the imply values.Frontiers in Molecular Biosciences | www.frontiersin.orgSeptember 2015 | Volume two | ArticleKorkuc and WaltherCompound-protein interactionsrotatable bond count (0.4), relative hydrogen bond acceptor (0.36)donor (0.22) count. Moreover, high isoelectric points (6.six) seems to promote selectivity. When inspected separately for the 3 compound classes (lines in Figure two), drugs stand out as exhibiting by far the most pronounced propensity profiles across all properties with largest absolute propensity values when compared with each metabolites and overlapping compounds with far more shallower profiles. In contrast to the monotonic profiles observed for the whole compound set, drugs display minimummaximum propensity curves for numerous properties. As drugs can be assumed to have been selected particularly against higher promiscuity, the minima for molecular weight (27859 Da), TPSA (topological polar surface area about, 9520 A2 ), strongest acidic pKa (four.90.1), relative sp3 hybridized carbons (0.11.three), relative Platt index (2.91.06), relative rotatable bonds (0.09.16), relative hydrogen bond acceptor (0.14.21)donor (0.06.11) count may perhaps correspond to optimal physicochemical properties imparting selectivity. In summary, promiscuous compounds with several binding divers events observed in the PDB have a tendency to be rather tiny, hydrophilic, and of low complexity allowing a superb match to extra diverse and little binding pockets. Also a flexible backbone (e.g., higher relative rotatable bond count and higher sp3 -hybridization level) enhances the capacity of compounds to bind to various target pockets. Furthermore, the increased number of hydrogen bond acceptors and donors in these compounds is advantageous for formation of interactions with target proteins. Drug compounds exhibit additional pronounced home propensities with regard to their promiscuity revealing also “sweet spots” associated with selective binding behavior. By contrast, metabolites and overlapping compounds exhibit shallow profiles with almost no apparent correlation with promiscuity.LogP and Compound Binding PromiscuityFor metabolites, no dependency of binding promiscuity on compound hydrophobicity as Mesitaldehyde Biological Activity measured by logP was detected, whereas for drugs, our analysis suggests that increasing hydrophobicity is negatively correlated with promiscuity (Figure 2, LogP), which can be contrary to literature reports that describe hydrophobic drugs as significantly less selective with regards to their binding to proteins (Peters, 2013). To further scrutinize our outcome, we analyzed the relation amongst hydrophobicity (logP) and promiscuity (pocket.