Motivated by recent experimental work on Leu-Enkephalin modification with (4-Carboxamido)phenylalanine (Cpa), we perform MD simulations to study the structure-activity relationships of the [Cpa1, Leu 5]-enkephalin (Cpa-LE) for better understandings of the binding affinity in δ-selective opioid ligands. Recently, Tyr1 substituted into Cpa1 form was experimentally found to be the first example of an amino acid that acts as a surrogate for Tyr1 in opioid peptide ligands, which challenges a long-standing belief that a phenolic residue is required for high affinity binding. Our simulations show the Cpa-LE structure in aqueous solution revealed that the occurrence of single-bend packed state can be stabilized by an intramolecular hydrogen bond from Leu 5-NH to Gly2-CO (5→2). In addition, an intramolecular sidechain to backbone hydrogen bond, i.e., hydrogen bond binding between the sidechain carbonyl CO group of the Cpa residue and backbone amide NH group of the Phe residue was examined. Furthermore, the hydration effects of carboxamido group (CONH2) for Cpa residue and 5→2 hydrogen bond were calculated via the solute-solvent radial distribution functions g α-β (r), providing direct evidence of strong hydrogen bond interactions. Our simulation results further reveal the χ1 rotamers of the Cpa1 and Phe4 that show preferences for trans and gauche (-), respectively. Finally, we elucidate the probability distributions of two aromatic rings among the Cpa-LE, Leu-enkephalin, and 8 pharmacophore model. The results show that modified the Tyr1 to Cpa1 can lead to increase the potency and selectivity for δ-opioid receptor (DOR), consistent with experimental findings.
All Science Journal Classification (ASJC) codes
- Organic Chemistry