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Better agonist for the opioid receptors
© The Author(s) 2018
Received: 18 November 2016
Accepted: 30 January 2018
Published: 8 February 2018
This commentary highlights the recent work published in journal Nature on the structural based discovery of novel analgesic compounds for opioid receptors with minimal effects. Manglik et al. selectively targeted the Gi based μOR pathway instead of the β-arrestin pathway of the opioids. The computational screening of millions of compounds showed a list of several competent ligands. From these ligands they synthesized the compounds with the best docking score, which were further optimized by adding side residues for better interaction with the μOR. A promising compound, PZM21, was a selective agonist of μOR. It has better analgesic properties with minimal side effects of respiratory depression and constipation. This work is a step towards better drug designing and synthesizing in terms of efficacy, specificity with least side effects of targeted GPCR proteins present in the human proteome.
Morphine is the natural alkaloid present in opium and it is obtained from poppy plant. Opium has been used as an analgesic and as a recreational drug since ancient times. Other common analgesics used include natural alkaloids like codeine, oxycodone, etc. where addiction and other side effects are an increasingly apparent social problem. Current progress in the discovery of different opioid receptors has helped the search for receptor specific drugs without adverse side effects. The protein data bank now contains high resolution structures of the μ, δ, к and nociception opioids receptor proteins [1–5]. The opioid receptors are G-protein coupled receptors (GPCRs), whose signaling is mediated through the G proteins . In the last few years, there has been a surge in high resolution X-ray crystallographic structures of GPCRs; particularly from the Kobilka research group at Stanford University. Whose work resulted in the Nobel Prize of Physiology in 2012 [6, 7].
The GPCR proteins are important players in eukaryotic signaling mechanisms [8, 9]. They transfer the message from extracellular side to the intracellular side of the cell across the plasma membrane [8, 9]. The common ligands for GPCRs includes lipids, fatty acids, neurotransmitters, photons, cytokines, hormones and metal ions [8, 9]. They transduce the signal across the plasma membrane by binding with these ligands that causes certain conformational changes into the seven trans-membrane alpha helices of GPCRs [8, 9]. The GPCR proteins are important drug targets and it is estimated that around 30% or more of the available marketed drugs are for GPCR related diseases . There is a general consensus that around 350 GPCRs are involved in various human diseases. Another ~ 100 GPCRs (called orphan GPCRs) have little information available about their natural ligands or physiological function . In the last few years several structures of GPCRs were computationally explored through molecular docking approaches to find suitable agonist and antagonist compounds that have no adverse effects [9, 11, 12]. Similarly, those GPCR whose X-ray crystallographic structures are not available were studied using the homology modeling techniques, where suitable ligands were docked with them based on virtual screening methods [9, 12].
In a recent study, Manglik et al. search for ideal opioid ligands that have lower side effects . They took around three million compounds from the ZINC database library [14, 15] and docked them with the orthosteric site of the μOR . Each compound has more than a million different configurations in the binding site that were considered. Most of the ligands interacted with the Aspartate147 of the orthosteric site of the protein . The top 2500 ligands were evaluated for their novelty and interaction with various internal residues. The new ligands selected have binding affinities in the micromolar (μM) range. These newly predicted ligands are cationic amines that mostly bind with μOR and show unique interactions of hydrogen bonding with Asp147, which was not reported before in the literature . For better binding affinity and selectivity, new analogues of these ligands were made. They retained the parent compound interaction with the receptor; however the additional side groups made new interactions in the binding site. The analogues that make several interactions in the molecular docking studies were synthesized in the laboratory for further studies .
Now with more powerful femtosecond serial X-ray crystallography, a number of high resolution crystal structures of GPCRs are available [17–19]. In the next few years we likely will have hundreds of high resolution structures of GPCRs from all of its different classes. Computational molecular docking approaches with highly selective agonists and antagonists will be available for each protein that will have minimal side effects . In crystal form, most GPCRs have an inactive state and there are always ambiguities in the interaction of agonist/antagonist with the protein. Molecular dynamics simulations should always be performed to get a more flexible and active state of GPCRs. The main advantages of structural based optimization and selection of ligands are that it saves both time and money in order to choose the best ligand for specific GPCR that work only through a single sided pathway in a biological system.
SLB and YNM wrote the manuscript while AU and SSA took part in discussion, suggestions and grammatical corrections for improvement of the manuscript. All authors read and approved the final manuscript.
We extend our sincere appreciation to the Deanship of Scientific Research at the King Saud University, Saudi Arabia for funding this work through Research Group No (RGP-007).
The authors decalre that they have no competing interests.
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