Compounds. Compounds 14 and 15, bearing a methionine side chain, showed a restricted
Compounds. Compounds 14 and 15, bearing a methionine side chain, showed a limited increment in the binding activity in comparison to compound 1. Notably, the introduction of aromatic substituents had a substantial influence on pIC50. Phenylalanine derivatives 16 and 17 resulted nearly ten instances more potent than LCA. Conversely, the replacement of phenylalanine with tyrosine led to poorly active compounds (18, 19) possibly resulting from their lower lipophilicity. The value of a lipophilic group at the position was further confirmed by the tryptophan conjugates 20 and 21, which had been significantly additional active than LCA. In specific, the L-Trp conjugate 20 showed a pIC50 of five.69, resulting essentially the most potent EphA2 ligand in the series. As the amino acid side chains of compounds two and 4-21 constitute a set having a big variation in each lipophilicity (just about 2 units) and steric bulk (40 MR units), we examined the statistical partnership between these properties plus the pIC50 values. A poor correlation was discovered for pIC50 with (r2 = 0.29) at the same time as with the steric TIP60 Formulation descriptor MR (r2 = 0.22). As a result, though it might be qualitatively inferred that hydrophobic interactions are crucial for potent ligands, side chain lipophilicity () appears inadequate to quantitatively clarify the variation in potency. The availability in the X-ray crystal structure of EphA2 in complex with the ephrin-A1 ligand34 prompted us to evaluate the existence of a correlation among experimental pIC50 and cost-free power of binding estimated by indicates of theoretical ADAM17 Inhibitor Molecular Weight solutions. Compounds two, 4-9 and 14-21 have been docked into the EphA2 binding website making use of the Glide software35 then, for every single of the resulting protein-ligand complexes, the binding totally free energy was estimated working with the MM-GBSA approach36 implemented in Prime,37 and the MM-PBSA approach38 implemented in Influence.39 These procedures employ a combination of molecular mechanics and continuum solvation to elicit binding free power directly from structural data at a affordable computational price. MM-GBSA is becoming a common tool to rescore docking poses within the field of structure-based drug design. Indeed, it provided improved enrichment in virtual screening of databases and superior correlation in between calculated binding affinities and experimentalNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptJ Med Chem. Author manuscript; offered in PMC 2014 April 11.Incerti et al.Pagedata in lead optimization of sets of congeneric inhibitors when in comparison with classical scoring function.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptThe docking strategy applied right here gave binding poses for the synthesized compounds superimposable to that of glycolithocholic acid 2 (Figure 2B). The resulting complexes highlighted the presence of an accessory hydrophobic website in the ligand-binding channel of your EphA2 receptor exactly where the -side chain on the conjugated derivatives may very well be accommodated. Such a binding mode can therefore clarify the lack of activity for the extra polar derivatives 10-13, as well as the considerable increment within the pIC50 values observed for the aromatic derivatives 16, 17, 20, and 21 bearing a phenylalanine or a tryptophan portion. Visual inspection with the EphA2-compound 20 complex further supported the value of aromatic interactions at the EphA2 receptor (Figure five). Indeed the indole ring of 20 tightly interacts with Phe108, a conserved residue responsible for the recognition.
