Are there physicochemical differences between allosteric and competitive ligands?

<div><p>Previous studies have compared the physicochemical properties of allosteric compounds to non-allosteric compounds. Those studies have found that allosteric compounds tend to be smaller, more rigid, more hydrophobic, and more drug-like than non-allosteric compounds. However, previous studies have not properly corrected for the fact that some protein targets have much more data than other systems. This generates concern regarding the possible skew that can be introduced by the inherent bias in the available data. Hence, this study aims to determine how robust the previous findings are to the addition of newer data. This study utilizes the Allosteric Database (ASD v3.0) and ChEMBL v20 to systematically obtain large datasets of both allosteric and competitive ligands. This dataset contains 70,219 and 9,511 unique ligands for the allosteric and competitive sets, respectively. Physically relevant compound descriptors were computed to examine the differences in their chemical properties. Particular attention was given to removing redundancy in the data and normalizing across ligand diversity and varied protein targets. The resulting distributions only show that allosteric ligands tend to be more aromatic and rigid and do not confirm the increase in hydrophobicity or difference in drug-likeness. These results are robust across different normalization schemes.</p></div

Weighting the data.

<p>In the top scheme, the center of each protein-ligand cluster is chosen, and only the centers are used to calculate the distribution of properties. In the bottom scheme, all ligands of each cluster contribute to the cluster’s normalized distribution of physical properties. The normalized distributions compensate for the different number of ligands in each cluster. The normalized distributions of all clusters are simply added to give the distribution of physical properties for the entire set of data.</p

The normalized distribution of heavy atoms for the ligands in the competitive set, with (brown, dashed line) and without (red, solid line) the seven kinase standards.

<p>The normalized distribution of heavy atoms for the ligands in the competitive set, with (brown, dashed line) and without (red, solid line) the seven kinase standards.</p

Clustering the data in two levels.

<p>The horizontal axis represents “protein space.” In the first step, similar proteins are grouped into families. The vertical axis represents “ligand space.” The second step clusters all the ligands associated with each protein in the protein family. The final boxes are the protein-ligand clusters used in normalizing the data.</p

ChemTreeMap [39] of the allosteric (blue) and competitive (red) ligands is a hierarchical tree based on grouping ligands by the Tc of the ECFP6 fingerprints.

<p>The size of each circle represents the number of ligands in a cluster of Tc ≥ 0.6. Though a few small regions of chemical space are dominated by one set or the other, the large number of branches with interdigitated red and blue circles shows that there is a great deal of chemical similarity between the allosteric and competitive ligands. To quantify the overlap, we should note that 623 out of 70,219 allosteric ligands (1%) are within Tc ≥ 0.6 of a competitive ligand, and 582 of the 9511 competitive ligands (6%) are within Tc ≥ 0.6 of an allosteric compound.</p

The number of protein families and their protein-ligand clusters at varying cutoffs for sequence (% identity) and chemical similarity as defined by the Tanimoto coeffficient (Tc) using the extended connectivity fingerprint (ECFP6).

<p>The number of protein families and their protein-ligand clusters at varying cutoffs for sequence (% identity) and chemical similarity as defined by the Tanimoto coeffficient (Tc) using the extended connectivity fingerprint (ECFP6).</p

Are there physicochemical differences between allosteric and competitive ligands? - Fig 4

<p>The distribution of protein targets for the allosteric (A) and competitive (B) compounds.</p

The 29 physicochemical properties that were compared between allosteric and competitive ligands.

<p>The 29 physicochemical properties that were compared between allosteric and competitive ligands.</p

SlogP versus the number of heavy atoms.

<p>Clustering was performed at 100% sequence identity and Tc = 1.0.</p

The normalized histograms of the number of aromatic atoms corrected by size, the number of bonds per heavy atom (HA), and the number of rotatable single bonds per HA for the full dataset (60%/0.6 clustering).

<p>The median (dashed line) is labeled on the graph with its 95%ci derived from bootstrap sampling.</p