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Bioactive conformations of two seminal delta opioid receptor penta-peptides inferred from free-energy profiles.

ABSTRACT: Delta-opioid (DOP) receptors are members of the G protein-coupled receptor (GPCR) sub-family of opioid receptors, and are evolutionarily related, with homology exceeding 70%, to cognate mu-opioid (MOP), kappa-opioid (KOP), and nociceptin opioid (NOP) receptors. DOP receptors are considered attractive drug targets for pain management because agonists at these receptors are reported to exhibit strong antinociceptive activity with relatively few side effects. Among the most potent analgesics targeting the DOP receptor are the linear and cyclic enkephalin analogs known as DADLE (Tyr-D-Ala-Gly-Phe-D-Leu) and DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen), respectively. Several computational and experimental studies have been carried out over the years to characterize the conformational profile of these penta-peptides with the ultimate goal of designing potent peptidomimetic agonists for the DOP receptor. The computational studies published to date, however, have investigated only a limited range of timescales and used over-simplified representations of the solvent environment. We provide here a thorough exploration of the conformational space of DADLE and DPDPE in an explicit solvent, using microsecond-scale molecular dynamics and bias-exchange metadynamics simulations. Free-energy profiles derived from these simulations point to a small number of DADLE and DPDPE conformational minima in solution, which are separated by relatively small energy barriers. Candidate bioactive forms of these peptides are selected from identified common spatial arrangements of key pharmacophoric points within all sampled conformations.

SUBMITTER: Scarabelli G

PROVIDER: S-EPMC3812360 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Bioactive conformations of two seminal delta opioid receptor penta-peptides inferred from free-energy profiles.

Scarabelli Guido G Provasi Davide D Negri Ana A Filizola Marta M

Biopolymers 20140101 1

Delta-opioid (DOP) receptors are members of the G protein-coupled receptor (GPCR) sub-family of opioid receptors, and are evolutionarily related, with homology exceeding 70%, to cognate mu-opioid (MOP), kappa-opioid (KOP), and nociceptin opioid (NOP) receptors. DOP receptors are considered attractive drug targets for pain management because agonists at these receptors are reported to exhibit strong antinociceptive activity with relatively few side effects. Among the most potent analgesics target ...[more]

PMID: 23564013

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Project description:Traditional assays that monitor cAMP inhibition by opioid receptor ligands require second-messenger accumulation over periods of 10-20 minutes. Since receptor regulation occurs within a similar time frame, such assays do not discriminate the actual signal from its modulation. Here we used bioluminescence resonance energy transfer to monitor inhibition of cAMP production by δ-opioid receptor (DOR) agonists in real time. cAMP inhibition elicited by different agonists over a period of 15 minutes was biphasic, with response buildup during the first 6 to 7 minutes, followed by a second phase of response decay or of no further increment. The rate at which the cAMP response disappeared was correlated with operational parameters describing ligand efficiency [log(τ/KA)] to promote Gαi activation, as well as with ligand ability to promote internalization during the time course of the assay. Thus, ligands that displayed low signaling efficiency and poor sequestration(SB235863 ([8R-(4bS*,8aα,8aβ,12bβ)]7,10-dimethyl-1-methoxy-11-(2-ethylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride), morphine) had minimal or no response decay. On the other hand, the decay rate was pronounced for deltorphin II, [d-Pen(2), d-pen(5)]-enkephalin, met-enkephalin, and SNC-80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide), which displayed high signaling efficiency and internalization. Moreover, inhibition of internalization by dynasore reduced or abolished response decay by internalizing ligands. Unlike acute responses, endocytic profiles were not predictive of whether an agonist would induce prolonged cAMP inhibition over sustained (30-120 minutes) DOR stimulation. Taken together, the data indicate that ligand ability to evoke G-protein activation or promote endocytosis was predictive of response duration over short, but not over sustained periods of cAMP inhibition.

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Bioactive conformations of two seminal delta opioid receptor penta-peptides inferred from free-energy profiles.

Publications

Bioactive conformations of two seminal delta opioid receptor penta-peptides inferred from free-energy profiles.

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