ErCompound-protein interactionsone or two binding events had been classified as “selective.” The final dataset comprised 2886 PDB DOTA-?NHS-?ester Autophagy compounds with a minimum of one non-redundant target pocket and 1226 of them classified as drugs, 659 as metabolites, and 1001 as both and therefore are termed “overlapping compounds” (Table 1A). 638 compounds (22 ) of those PDB compounds are promiscuous. They include things like 114 drugs, 129 metabolites, and 395 overlapping compounds, which altogether interact with 9774 target pockets (Table 1B). As already evident in the statistic, drug compounds are substantially additional selective, with 9.three qualifying as promiscuous, than metabolites (19.5 promiscuous).Physicochemical Properties of Metabolites and Drugs Bound to ProteinsIn order to characterize metabolites, drugs, and overlapping compounds with regard to particular physicochemical properties governing their protein binding behavior, we computed a array of relevant properties commonly made use of within the field of cheminformatics (Supplementary Table 1 includes a list in addition to definitions) for all compounds inside the respective sets and tested them for substantial frequency distribution variations applying the two-sample Kolmogorov-Smirnov test (Figure 1) (Lilliefors, 1967). Across the set of physicochemical properties examined, drug compounds possess distinctive characteristics when compared with each metabolites and overlapping compounds, whereas the set of compounds classified as both drugs and metabolites (overlapping compounds) are a lot more comparable to metabolites than to drugs (Figure 1). On typical, the drug compounds utilized here are larger than metabolites with larger values for molecular weight (medians of 330.2Da vs. 238.7Da for drugs and metabolites, respectively, pWilcox = 1.2E-19), atom count (38 vs. 30, p = 6.7E-12), ring atom count (12 vs. 6, p = 2.0E-35), accessible surface region (ASA) (514.6 vs. 394.4 , p = three.7E-23), have fewer hydrogen bond donors (0.12 vs. 0.18, p = 1.7E-15), and acceptors (0.23 vs. 0.3, p = five.2E-09) when normalized for size, and carry each weaker acidic and simple functional groups [higher strongest acidic (8.89 vs. four.36, p = 9.7E-06) and simple (2.28 vs. -1.53, p = four.4E-09) pKa ] and may for that reason be assumed much less charged at physiological pH. Reduced polarity and charge of drugs is also mirrored by their improved hydrophobicity [higher logP (octanol partition coefficient)] relative to metabolites (1.43 vs. -0.three, p = 3.2E-13). A comparatively large quantity of drugs appears to be positively charged at neutral pH (secondary peak with the isoelectric point distribution about pI = 9), although metabolites predominantly carry unfavorable charges at neutral pH. The topological polar surface location (TPSA) seems similar for all compound classes (median of 90 ). Even so, as drugs are, on typical, bigger and have larger ASA, the reduced polarity of drugs relative to metabolites is evident again. Although the mode of the relative rotatable bond count density distribution is similar for all three compound classes, drugs possess distinctly a lot more ring atoms relative to their size (higher relative ring atom count: 0.56 vs. 0.46, p = eight.6E-18) and relatively fewer sp3 -hybridized carbon atoms (0.33 vs. 0.53, p = two.6E-16). Many graph-based measures have turn out to be well-liked inside the field of cheminformatics to describe the topologies ofcompounds (see Supplementary Table 1 for short descriptions). The Balaban index is smaller sized for drugs than for metabolites reflecting the enhanced ring atom count (1.69 vs. two.12,.
