Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation

Abstract

<jats:p>Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W2936.48 (Ballesteros–Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W3187.35, Y3267.43, and Y3367.53 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR–ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.</jats:p>

Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl—Simulated Interaction Patterns Confronted with Experimental Data

“…As shown in Figure 4 , all ligands consistently make contact with D147 3x32 and the sixth transmembrane helix (TM6) of the µ opioid receptor for the 4DKL and 5C1M crystal structures. These observations are consistent with the very recent work of Zhao et al [ 27 ], where docking and MD simulations were carried out for PZM21, TRV130 (oliceridine), and morphine using one crystal structure (5C1M) to explain the differences in their functional profiles. On the other hand, the docking poses obtained for 6DDF did not make such frequent contact with TM6—fentanyl made contact with three residues from this protein region, and PZM21 and SR-17018 interacted only with W293 6×48 and I296 6×51.…”

“…Strong interaction of the modeled compounds with D147 3×32 was also reported by Zhao et al [ 27 ]. This finding is consistent for simulations carried out for all crystal structures.…”

“…Analyzing the contact patterns presented in Figure 6 , one can see that the characteristic MD simulation output is the very strong interaction of PZM21 with D147 3×32 , even during the simulation with 6DDF, where the compound orientation was in general very unstable (analogous observation also reported by Zhao et al [ 27 ]). Many research studies have indicated this residue as very important for activity towards the µ opioid receptor [ 29 , 30 ].…”

“…Similarly, in our simulations with 5C1M (crystal structure used by Zhao et al), morphine made contact with H297 6×52 after ~200 ns of simulation, which was maintained consistently until the end of the simulation by ~1800 ns. On the other hand, PZM21 also came into short contact with this residue (~300–500 ns), but then the interaction was lost and the compound did not interact with H297 6×52 , as reported by Zhao et al [ 27 ].…”

“…Zhao et al indicated W293 6×48 , W318 7×35 , Y326 7×42 , and Y336 7×53 as residues that affect the receptor function [ 27 ]. These positions were not indicated in our statistical analyses; however, it should be pointed out that the method of residue indication in our study differed from Zhao’s approach.…”