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 restricted increment in the binding activity in comparison with compound 1. Notably, the introduction of aromatic substituents had a substantial impact on pIC50. Phenylalanine derivatives 16 and 17 resulted practically ten instances much more potent than LCA. Conversely, the replacement of phenylalanine with tyrosine led to poorly active compounds (18, 19) possibly resulting from their decrease lipophilicity. The importance of a lipophilic group at the position was additional confirmed by the tryptophan conjugates 20 and 21, which have been considerably a lot more active than LCA. In unique, the L-Trp conjugate 20 showed a pIC50 of 5.69, resulting probably the most potent EphA2 ligand of your series. As the amino acid side chains of compounds two and 4-21 constitute a set having a substantial variation in both lipophilicity (just about two units) and steric bulk (40 MR units), we examined the statistical connection 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 descriptor MR (r2 = 0.22). Consequently, whilst it could possibly be qualitatively inferred that hydrophobic interactions are critical for potent ligands, side chain lipophilicity () appears inadequate to quantitatively explain the variation in potency. The availability from the X-ray crystal structure of EphA2 in complex together with the ephrin-A1 ligand34 prompted us to evaluate the existence of a correlation amongst experimental pIC50 and totally free energy of binding estimated by suggests of theoretical methods. Compounds 2, 4-9 and 14-21 had been PKCθ site docked into the EphA2 binding site applying the Glide software35 then, for every single of the resulting protein-ligand complexes, the binding absolutely free power was estimated applying the MM-GBSA approach36 implemented in Prime,37 and also the MM-PBSA approach38 implemented in Effect.39 These procedures employ a combination of molecular mechanics and continuum solvation to elicit binding no cost power straight from structural info at a affordable computational price. MM-GBSA is becoming a normal tool to rescore docking poses in the field of structure-based drug design and style. Indeed, it provided enhanced enrichment in virtual screening of databases and superior correlation between calculated binding affinities and experimentalNIH-PA Author αvβ5 Biological Activity Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptJ Med Chem. Author manuscript; obtainable in PMC 2014 April 11.Incerti et al.Pagedata in lead optimization of sets of congeneric inhibitors when compared to classical scoring function.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptThe docking approach applied right here gave binding poses for the synthesized compounds superimposable to that of glycolithocholic acid two (Figure 2B). The resulting complexes highlighted the presence of an accessory hydrophobic website within the ligand-binding channel with the EphA2 receptor where the -side chain on the conjugated derivatives might be accommodated. Such a binding mode can hence explain the lack of activity for the much more polar derivatives 10-13, as well because the important increment in the pIC50 values observed for the aromatic derivatives 16, 17, 20, and 21 bearing a phenylalanine or a tryptophan portion. Visual inspection on the EphA2-compound 20 complex further supported the significance of aromatic interactions in the EphA2 receptor (Figure five). Indeed the indole ring of 20 tightly interacts with Phe108, a conserved residue responsible for the recognition.
