Structure-activity relationships of Leu-Enkephalin analog with (4-Carboxamido)phenylalanine substituted for tyrosine: a molecular dynamics study.

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 [Cpa(1), Leu(5)]-enkephalin (Cpa-LE) for better understandings of the binding affinity in delta-selective opioid ligands. Recently, Tyr(1) substituted into Cpa(1) form was experimentally found to be the first example of an amino acid that acts as a surrogate for Tyr(1) 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 Gly(2)-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 (CONH(2)) for Cpa residue and 5-->2 hydrogen bond were calculated via the solute-solvent radial distribution functions g(alpha-beta) (r), providing direct evidence of strong hydrogen bond interactions. Our simulation results further reveal the chi(1) rotamers of the Cpa(1) and Phe(4) 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 delta pharmacophore model. The results show that modified the Tyr(1) to Cpa(1) can lead to increase the potency and selectivity for delta-opioid receptor (DOR), consistent with experimental findings.