RESUMEN
In the present work, a series of simulation tools were used to determine structure-activity relationships for the endomorphins (EMs) and derive µ-pharmacophore models for these peptides. Potential lowest energy conformations were determined in vacuo by systematically varying the torsional angles of the Tyr(1)-Pro(2) (ω(1)) and Pro(2)-Trp(3)/Phe(3) (ω(2)) as tuning parameters in AM1 calculations. These initial models were then exposed to aqueous conditions via molecular dynamics simulations. In aqueous solution, the simulations suggest that endomorphin conformers strongly favor the trans/trans pair of the ω(1)/ω(2) amide bonds. From two-dimensional probability distributions of the ring-to-ring distances with respect to the pharmacophoric angles for EMs, a selectivity range of µ(1) is ca. 8.3 ~ 10.5 Å for endomorphin-2 and selectivity range of µ(2) is ca. 10.5 ~ 13.0 Å for endomorphin-1 were determined. Four-component µ-pharmacophore models are proposed for EMs and are compared to the previously published δ- and κ-pharmacophore models.
Asunto(s)
Simulación de Dinámica Molecular , Oligopéptidos/química , Receptores Opioides mu/química , Enlace de Hidrógeno , Conformación Proteica , SolucionesRESUMEN
This paper investigates the structure-activity relationships of alphaS1-casomorphin (alphaS1-CM) using AM1 calculations and molecular dynamics (MD) simulations. Previous studies have shown that this peptide has remarkable opioid actions, and not only has a high affinity toward all three subtypes (kappa1-kappa3) of the kappa-opioid sites, but also inhibits the proliferation of the T47D human breast cancer cell line. The systematic conformer search performed by the AM1 calculations is based on the torsional angles of the Val2-Pro3 (omega2) and Phe4-Pro5 (omega4) amide bonds. The AM1 results reveal that the alphaS1-CM conformers strongly favor the cis/cis pair of the omega2/omega4 amide bonds in the minimized energy state. Furthermore, the picture of these stable conformers is found to be a strong interaction of the coulomb's force between two terminuses. MD simulations are performed to investigate the features of both the structural stability and pharmacological activity of alphaS1-CM in aqueous solution. The simulation results reveal that the omega2/omega4 amide bonds favor the cis/cis status in the stable state. Furthermore, the pharmacophoric distance between two aromatic rings is found to be 5.0 approximately 5.4A. The chi1 rotamers of the Tyr and Phe residues show a preference for gauche (-) and trans, respectively. The side chain rotamers of alphaS1-CM are competed to those of other opioid ligands with a known potency and selectivity for delta- and mu-opioid receptors. Finally, we address a likely kappa pharmacophore model compared to the delta pharmacophore model.
Asunto(s)
Caseínas/química , Caseínas/farmacología , Simulación por Computador , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Ligandos , Modelos Químicos , Estructura Molecular , Receptores Opioides/metabolismo , Soluciones , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Analgésicos Opioides/química , Encefalina Leucina/química , Fenilalanina/análogos & derivados , Fenilalanina/química , Tirosina/química , Simulación por Computador , Enlace de Hidrógeno , Conformación Molecular , Estructura Molecular , Receptores Opioides delta/química , Soluciones , Relación Estructura-Actividad , Agua/químicaRESUMEN
The conformational stability of the extended antiparallel dimer structure of Met-enkephalin in water was analyzed by examining the hydration structure of enkephalin using molecular dynamics simulations. The result shows that, despite of the hydrophicility of the terminal atoms in the pentapeptide, the main contributor for the stability of the dimer in water is the four intermolecular hydrogen bonds between the Gly(2) and Phe(4) groups. The three-dimensional model of the delta-opioid pharmacophore for this dimer structure was also established. Such a model was demonstrated to match the delta-opioid pharmacophore query derived from the non-peptides SIOM, TAN-67, and OMI perfectly. This result thus strongly supports the assumption that the dimer structure of Met-enkephalin is a possible delta-receptor binding conformation.