Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors
Abstract
1. Introduction
2. Current Structural Insight in δOR Binding Pocket and Activation Mechanism
3. Limitations of Current δOR Structures
4. Opportunities for Computer-Aided Drug Discovery at the δOR
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Erspamer, V.; Melchiorri, P.; Falconieri-Erspamer, G.; Negri, L.; Corsi, R.; Severini, C.; Barra, D.; Simmaco, M.; Kreil, G. Deltorphins: A family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites. Proc. Natl. Acad. Sci. USA 1989, 86, 5188–5192. [Google Scholar] [CrossRef] [PubMed]
- Fricker, L.D.; Margolis, E.B.; Gomes, I.; Devi, L.A. Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions. Mol. Pharmacol. 2020, 98, 96–108. [Google Scholar] [CrossRef] [PubMed]
- Cassell, R.J.; Mores, K.L.; Zerfas, B.L.; Mahmoud, A.H.; Lill, M.A.; Trader, D.J.; van Rijn, R.M. Rubiscolins are naturally occurring G protein-biased delta opioid receptor peptides. Eur. Neuropsychopharmacol. 2019, 29, 450–456. [Google Scholar] [CrossRef] [PubMed]
- Gutridge, A.M.; Robins, M.T.; Cassell, R.J.; Uprety, R.; Mores, K.L.; Ko, M.J.; Pasternak, G.W.; Majumdar, S.; van Rijn, R.M. G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder. Br. J. Pharmacol. 2019, 177, 1497–1513. [Google Scholar] [CrossRef] [PubMed]
- Gutridge, A.M.; Chakraborty, S.; Varga, B.R.; Rhoda, E.S.; French, A.R.; Blaine, A.T.; Royer, Q.H.; Cui, H.; Yuan, J.; Cassell, R.J.; et al. Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder. Front. Pharmacol. 2021, 12, 764885. [Google Scholar] [CrossRef] [PubMed]
- Gendron, L.; Cahill, C.M.; von Zastrow, M.; Schiller, P.W.; Pineyro, G. Molecular Pharmacology of delta-Opioid Receptors. Pharmacol. Rev. 2016, 68, 631–700. [Google Scholar] [CrossRef]
- Pradhan, A.A.; Befort, K.; Nozaki, C.; Gaveriaux-Ruff, C.; Kieffer, B.L. The delta opioid receptor: An evolving target for the treatment of brain disorders. Trends Pharmacol. Sci. 2011, 32, 581–590. [Google Scholar] [CrossRef]
- Grant Liska, M.; Crowley, M.G.; Lippert, T.; Corey, S.; Borlongan, C.V. Delta Opioid Receptor and Peptide: A Dynamic Therapy for Stroke and Other Neurological Disorders. Handb. Exp. Pharmacol. 2017, 247, 277–299. [Google Scholar]
- Mabrouk, O.S.; Marti, M.; Salvadori, S.; Morari, M. The novel delta opioid receptor agonist UFP-512 dually modulates motor activity in hemiparkinsonian rats via control of the nigro-thalamic pathway. Neuroscience 2009, 164, 360–369. [Google Scholar] [CrossRef]
- Sarajarvi, T.; Marttinen, M.; Natunen, T.; Kauppinen, T.; Makinen, P.; Helisalmi, S.; Laitinen, M.; Rauramaa, T.; Leinonen, V.; Petaja-Repo, U.; et al. Genetic Variation in delta-Opioid Receptor Associates with Increased beta- and gamma-Secretase Activity in the Late Stages of Alzheimer’s Disease. J. Alzheimers Dis. 2015, 48, 507–516. [Google Scholar] [CrossRef]
- Crist, R.C.; Clarke, T.K. OPRD1 Genetic Variation and Human Disease. Handb. Exp. Pharmacol. 2018, 247, 131–145. [Google Scholar] [PubMed]
- Johnston, T.H.; Versi, E.; Howson, P.A.; Ravenscroft, P.; Fox, S.H.; Hill, M.P.; Reidenberg, B.E.; Corey, R.; Brotchie, J.M. DPI-289, a novel mixed delta opioid agonist/mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson’s disease. Neuropharmacology 2018, 131, 116–127. [Google Scholar] [CrossRef] [PubMed]
- Xu, Y.; Zhi, F.; Mao, J.; Peng, Y.; Shao, N.; Balboni, G.; Yang, Y.; Xia, Y. delta-opioid receptor activation protects against Parkinson’s disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy. Aging 2020, 12, 25035–25059. [Google Scholar] [CrossRef] [PubMed]
- Alongkronrusmee, D.; Chiang, T.; van Rijn, R.M. Delta Opioid Pharmacology in Relation to Alcohol Behaviors. Handb. Exp. Pharmacol. 2016, 247, 199–225. [Google Scholar]
- Chiang, T.; Sansuk, K.; van Rijn, R.M. beta-Arrestin 2 dependence of delta opioid receptor agonists is correlated with alcohol intake. Br. J. Pharmacol. 2016, 173, 332–343. [Google Scholar] [CrossRef]
- Robins, M.T.; Chiang, T.; Mores, K.L.; Alongkronrusmee, D.; van Rijn, R.M. Critical Role for Gi/o-Protein Activity in the Dorsal Striatum in the Reduction of Voluntary Alcohol Intake in C57Bl/6 Mice. Front. Psychiatry 2018, 9, 112. [Google Scholar] [CrossRef]
- Corsetti, M.; Whorwell, P. New therapeutic options for IBS: The role of the first in class mixed micro- opioid receptor agonist and delta-opioid receptor antagonist (mudelta) eluxadoline. Expert Rev. Gastroenterol. Hepatol. 2017, 11, 285–292. [Google Scholar] [CrossRef]
- DiCello, J.J.; Carbone, S.E.; Saito, A.; Pham, V.; Szymaszkiewicz, A.; Gondin, A.B.; Alvi, S.; Marique, K.; Shenoy, P.; Veldhuis, N.A.; et al. Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders. Am. J. Physiol. Gastrointest. Liver Physiol. 2022, 322, G66–G78. [Google Scholar] [CrossRef]
- Dondio, G. Development of novel pain relief agents acting through the selective activation of the delta-opioid receptor. Farmaco 2000, 55, 178–180. [Google Scholar] [CrossRef]
- Kotzer, C.J.; Hay, D.W.; Dondio, G.; Giardina, G.; Petrillo, P.; Underwood, D.C. The antitussive activity of delta-opioid receptor stimulation in guinea pigs. J. Pharmacol. Exp. Ther. 2000, 292, 803–809. [Google Scholar]
- Petrillo, P.; Angelici, O.; Bingham, S.; Ficalora, G.; Garnier, M.; Zaratin, P.F.; Petrone, G.; Pozzi, O.; Sbacchi, M.; Stean, T.O.; et al. Evidence for a selective role of the delta-opioid agonist [8R-(4bS*,8aalpha,8abeta, 12bbeta)]7,10-Dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoli ne hydrochloride (SB-235863) in blocking hyperalgesia associated with inflammatory and neuropathic pain responses. J. Pharmacol. Exp. Ther. 2003, 307, 1079–1089. [Google Scholar] [PubMed]
- Richards, E.M.; Mathews, D.C.; Luckenbaugh, D.A.; Ionescu, D.F.; Machado-Vieira, R.; Niciu, M.J.; Duncan, W.C.; Nolan, N.M.; Franco-Chaves, J.A.; Hudzik, T.; et al. A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology 2016, 233, 1119–1130. [Google Scholar] [CrossRef] [PubMed]
- Cubist Pharmaceuticals LLC. Analgesic Efficacy and Safety of ADL5859 in Subjects With Acute Dental Pain After Third Molar Extraction. Available online: https://clinicaltrials.gov/ct2/show/NCT00993863 (accessed on 12 July 2022).
- Cubist Pharmaceuticals LLC. Study to Assess the Efficacy, Safety, and Tolerability of ADL5747 in Participants With Postherpetic Neuralgia. Available online: https://clinicaltrials.gov/ct2/show/NCT01058642 (accessed on 12 July 2022).
- Broom, D.C.; Jutkiewicz, E.M.; Folk, J.E.; Traynor, J.R.; Rice, K.C.; Woods, J.H. Convulsant activity of a non-peptidic delta-opioid receptor agonist is not required for its antidepressant-like effects in Sprague-Dawley rats. Psychopharmacology 2002, 164, 42–48. [Google Scholar] [CrossRef] [PubMed]
- Vicente-Sanchez, A.; Dripps, I.J.; Tipton, A.F.; Akbari, H.; Akbari, A.; Jutkiewicz, E.M.; Pradhan, A.A. Tolerance to high-internalizing delta opioid receptor agonist is critically mediated by arrestin 2. Br. J. Pharmacol. 2018, 175, 3050–3059. [Google Scholar] [CrossRef]
- Jutkiewicz, E.M.; Rice, K.C.; Traynor, J.R.; Woods, J.H. Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats. Psychopharmacology 2005, 182, 588–596. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Codd, E.E.; Carson, J.R.; Colburn, R.W.; Stone, D.J.; Van Besien, C.R.; Zhang, S.P.; Wade, P.R.; Gallantine, E.L.; Meert, T.F.; Molino, L.; et al. JNJ-20788560 [9-(8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide], a selective delta opioid receptor agonist, is a potent and efficacious antihyperalgesic agent that does not produce respiratory depression, pharmacologic tolerance, or physical dependence. J. Pharmacol. Exp. Ther. 2009, 329, 241–251. [Google Scholar]
- Codd, E.E.; Carson, J.R.; Colburn, R.W.; Dax, S.L.; Desai-Krieger, D.; Martinez, R.P.; McKown, L.A.; Neilson, L.A.; Pitis, P.M.; Stahle, P.L.; et al. The novel, orally active, delta opioid RWJ-394674 is biotransformed to the potent mu opioid RWJ-413216. J. Pharmacol. Exp. Ther. 2006, 318, 1273–1279. [Google Scholar] [CrossRef]
- Holt, J.D.; Watson, M.J.; Chang, J.P.; O’Neill, S.J.; Wei, K.; Pendergast, W.; Gengo, P.J.; Chang, K.J. DPI-221 [4-((alpha-s)-alpha-((2s,5r)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl )-N,N-diethylbenzamide]: A novel nonpeptide delta receptor agonist producing increased micturition interval in normal rats. J. Pharmacol. Exp. Ther. 2005, 315, 601–608. [Google Scholar] [CrossRef]
- Yi, S.P.; Kong, Q.H.; Li, Y.L.; Pan, C.L.; Yu, J.; Cui, B.Q.; Wang, Y.F.; Wang, G.L.; Zhou, P.L.; Wang, L.L.; et al. The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability. Acta Pharmacol. Sin. 2017, 38, 977–989. [Google Scholar] [CrossRef]
- Cassell, R.J.; Sharma, K.K.; Su, H.; Cummins, B.R.; Cui, H.; Mores, K.L.; Blaine, A.T.; Altman, R.A.; van Rijn, R.M. The Meta-Position of Phe(4) in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors. Molecules 2019, 24, 4542. [Google Scholar] [CrossRef]
- Vezzi, V.; Onaran, H.O.; Molinari, P.; Guerrini, R.; Balboni, G.; Calo, G.; Costa, T. Ligands raise the constraint that limits constitutive activation in G protein-coupled opioid receptors. J. Biol. Chem. 2013, 288, 23964–23978. [Google Scholar] [CrossRef] [PubMed]
- Bella Ndong, D.; Blais, V.; Holleran, B.J.; Proteau-Gagné, A.; Cantin-Savoie, I.; Robert, W.; Nadon, J.-F.; Beauchemin, S.; Leduc, R.; Piñeyro, G.; et al. Exploration of the fifth position of leu-enkephalin and its role in binding and activating delta (DOP) and mu (MOP) opioid receptors. Pept. Sci. 2019, 111, e24070. [Google Scholar] [CrossRef]
- Sharma, K.K.; Cassell, R.J.; Meqbil, Y.J.; Su, H.; Blaine, A.T.; Cummins, B.R.; Mores, K.L.; Johnson, D.K.; van Rijn, R.M.; Altman, R.A. Modulating beta-arrestin 2 recruitment at the delta- and mu-opioid receptors using peptidomimetic ligands. RSC Med. Chem. 2021, 12, 1958–1967. [Google Scholar] [CrossRef] [PubMed]
- Conibear, A.E.; Asghar, J.; Hill, R.; Henderson, G.; Borbely, E.; Tekus, V.; Helyes, Z.; Palandri, J.; Bailey, C.; Starke, I.; et al. A Novel G Protein-Biased Agonist at the delta Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain. J. Pharmacol. Exp. Ther. 2020, 372, 224–236. [Google Scholar] [CrossRef]
- Crombie, A.; Arezzo, J.; Cowan, C.; DeWire, S.; Gowen-McDonald, W.; Hawkins, M.; Jutkiewicz, E.; Kramer, M.; Koblish, M.; Lark, M.; et al. TRV250: A novel G protein-biased ligand at the delta receptor for the potential treatment of migraine. Postgrad. Med. 2015, 127 (Suppl. 1), S61. [Google Scholar]
- Nagase, H.; Nemoto, T.; Matsubara, A.; Saito, M.; Yamamoto, N.; Osa, Y.; Hirayama, S.; Nakajima, M.; Nakao, K.; Mochizuki, H.; et al. Design and synthesis of KNT-127, a delta-opioid receptor agonist effective by systemic administration. Bioorg. Med. Chem. Lett. 2010, 20, 6302–6305. [Google Scholar] [CrossRef]
- Knapp, R.J.; Landsman, R.; Waite, S.; Malatynska, E.; Varga, E.; Haq, W.; Hruby, V.J.; Roeske, W.R.; Nagase, H.; Yamamura, H.I. Properties of TAN-67, a nonpeptidic delta-opioid receptor agonist, at cloned human delta- and mu-opioid receptors. Eur. J. Pharmacol. 1995, 291, 129–134. [Google Scholar] [CrossRef]
- Burford, N.T.; Clark, M.J.; Wehrman, T.S.; Gerritz, S.W.; Banks, M.; O’Connell, J.; Traynor, J.R.; Alt, A. Discovery of positive allosteric modulators and silent allosteric modulators of the mu-opioid receptor. Proc. Natl. Acad. Sci. USA 2013, 110, 10830–10835. [Google Scholar] [CrossRef]
- Burford, N.T.; Livingston, K.; Canals, M.; Ryan, M.; Budenholzer, L.; Han, Y.; Shang, Y.; Herbst, J.J.; O’Connell, J.; Banks, M.; et al. Discovery, Synthesis and Molecular Pharmacology of Selective Positive Allosteric Modulators of the delta-Opioid Receptor. J. Med. Chem. 2015, 58, 4220–4229. [Google Scholar] [CrossRef]
- Stanczyk, M.A.; Livingston, K.E.; Chang, L.; Weinberg, Z.Y.; Puthenveedu, M.A.; Traynor, J.R. The delta-opioid receptor positive allosteric modulator BMS 986187 is a G-protein-biased allosteric agonist. Br. J. Pharmacol. 2019, 176, 1649–1663. [Google Scholar] [CrossRef]
- Fujii, H.; Uchida, Y.; Shibasaki, M.; Nishida, M.; Yoshioka, T.; Kobayashi, R.; Honjo, A.; Itoh, K.; Yamada, D.; Hirayama, S.; et al. Discovery of delta opioid receptor full agonists lacking a basic nitrogen atom and their antidepressant-like effects. Bioorg. Med. Chem. Lett. 2020, 30, 127176. [Google Scholar] [CrossRef] [PubMed]
- Meqbil, Y.J.; Su, H.; Cassell, R.J.; Mores, K.L.; Gutridge, A.M.; Cummins, B.R.; Chen, L.; van Rijn, R.M. Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities. Molecules 2021, 26, 7236. [Google Scholar] [CrossRef] [PubMed]
- Evans, C.J.; Keith, D.E., Jr.; Morrison, H.; Magendzo, K.; Edwards, R.H. Cloning of a delta opioid receptor by functional expression. Science 1992, 258, 1952–1955. [Google Scholar] [CrossRef] [PubMed]
- Kieffer, B.L.; Befort, K.; Gaveriaux-Ruff, C.; Hirth, C.G. The delta-opioid receptor: Isolation of a cDNA by expression cloning and pharmacological characterization. Proc. Natl. Acad. Sci. USA 1992, 89, 12048–12052. [Google Scholar] [CrossRef]
- Ballesteros, J.A.; Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci. 1995, 25, 366–428. [Google Scholar]
- Kong, H.; Raynor, K.; Yasuda, K.; Moe, S.T.; Portoghese, P.S.; Bell, G.I.; Reisine, T. A single residue, aspartic acid 95, in the delta opioid receptor specifies selective high affinity agonist binding. J. Biol. Chem. 1993, 268, 23055–23058. [Google Scholar] [CrossRef]
- Befort, K.; Tabbara, L.; Bausch, S.; Chavkin, C.; Evans, C.; Kieffer, B. The conserved aspartate residue in the third putative transmembrane domain of the delta-opioid receptor is not the anionic counterpart for cationic opiate binding but is a constituent of the receptor binding site. Mol. Pharmacol. 1996, 49, 216–223. [Google Scholar]
- Befort, K.; Tabbara, L.; Kling, D.; Maigret, B.; Kieffer, B.L. Role of aromatic transmembrane residues of the delta-opioid receptor in ligand recognition. J. Biol. Chem. 1996, 271, 10161–10168. [Google Scholar] [CrossRef]
- Onogi, T.; Minami, M.; Katao, Y.; Nakagawa, T.; Aoki, Y.; Toya, T.; Katsumata, S.; Satoh, M. DAMGO, a mu-opioid receptor selective agonist, distinguishes between mu- and delta-opioid receptors around their first extracellular loops. FEBS Lett. 1995, 357, 93–97. [Google Scholar] [CrossRef]
- Minami, M.; Nakagawa, T.; Seki, T.; Onogi, T.; Aoki, Y.; Katao, Y.; Katsumata, S.; Satoh, M. A single residue, Lys108, of the delta-opioid receptor prevents the mu-opioid-selective ligand [D-Ala2,N-MePhe4,Gly-ol5]enkephalin from binding to the delta-opioid receptor. Mol. Pharmacol. 1996, 50, 1413–1422. [Google Scholar]
- Valiquette, M.; Vu, H.K.; Yue, S.Y.; Wahlestedt, C.; Walker, P. Involvement of Trp-284, Val-296, and Val-297 of the human delta-opioid receptor in binding of delta-selective ligands. J. Biol. Chem. 1996, 271, 18789–18796. [Google Scholar] [CrossRef] [PubMed]
- Strahs, D.; Weinstein, H. Comparative modeling and molecular dynamics studies of the delta, kappa and mu opioid receptors. Protein Eng. 1997, 10, 1019–1038. [Google Scholar] [CrossRef] [PubMed]
- Decaillot, F.M.; Befort, K.; Filliol, D.; Yue, S.; Walker, P.; Kieffer, B.L. Opioid receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation. Nat. Struct. Biol. 2003, 10, 629–636. [Google Scholar] [CrossRef] [PubMed]
- Granier, S.; Manglik, A.; Kruse, A.C.; Kobilka, T.S.; Thian, F.S.; Weis, W.I.; Kobilka, B.K. Structure of the delta-opioid receptor bound to naltrindole. Nature 2012, 485, 400–404. [Google Scholar] [CrossRef] [PubMed]
- Fenalti, G.; Giguere, P.M.; Katritch, V.; Huang, X.P.; Thompson, A.A.; Cherezov, V.; Roth, B.L.; Stevens, R.C. Molecular control of delta-opioid receptor signalling. Nature 2014, 506, 191–196. [Google Scholar] [CrossRef]
- Chavkin, C.; Goldstein, A. Specific receptor for the opioid peptide dynorphin: Structure—Activity relationships. Proc. Natl. Acad. Sci. USA 1981, 78, 6543–6547. [Google Scholar] [CrossRef]
- Fenalti, G.; Zatsepin, N.A.; Betti, C.; Giguere, P.; Han, G.W.; Ishchenko, A.; Liu, W.; Guillemyn, K.; Zhang, H.; James, D.; et al. Structural basis for bifunctional peptide recognition at human delta-opioid receptor. Nat. Struct. Mol. Biol. 2015, 22, 265–268. [Google Scholar] [CrossRef]
- Varga, E.V.; Li, X.; Stropova, D.; Zalewska, T.; Landsman, R.S.; Knapp, R.J.; Malatynska, E.; Kawai, K.; Mizusura, A.; Nagase, H.; et al. The third extracellular loop of the human delta-opioid receptor determines the selectivity of delta-opioid agonists. Mol. Pharmacol. 1996, 50, 1619–1624. [Google Scholar]
- Claff, T.; Yu, J.; Blais, V.; Patel, N.; Martin, C.; Wu, L.; Han, G.W.; Holleran, B.J.; Van der Poorten, O.; White, K.L.; et al. Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists. Sci. Adv. 2019, 5, eaax9115. [Google Scholar] [CrossRef]
- Kooistra, A.J.; Mordalski, S.; Pandy-Szekeres, G.; Esguerra, M.; Mamyrbekov, A.; Munk, C.; Keseru, G.M.; Gloriam, D.E. GPCRdb in 2021: Integrating GPCR sequence, structure and function. Nucleic Acids Res. 2021, 49, D335–D343. [Google Scholar] [CrossRef]
- Munk, C.; Harpsoe, K.; Hauser, A.S.; Isberg, V.; Gloriam, D.E. Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr. Opin. Pharmacol. 2016, 30, 51–58. [Google Scholar] [CrossRef] [PubMed]
- Danev, R.; Belousoff, M.; Liang, Y.L.; Zhang, X.; Eisenstein, F.; Wootten, D.; Sexton, P.M. Routine sub-2.5 A cryo-EM structure determination of GPCRs. Nat. Commun. 2021, 12, 4333. [Google Scholar] [CrossRef] [PubMed]
- Draper-Joyce, C.J.; Khoshouei, M.; Thal, D.M.; Liang, Y.L.; Nguyen, A.T.N.; Furness, S.G.B.; Venugopal, H.; Baltos, J.A.; Plitzko, J.M.; Danev, R.; et al. Structure of the adenosine-bound human adenosine A1 receptor-Gi complex. Nature 2018, 558, 559–563. [Google Scholar] [CrossRef] [PubMed]
- Che, T.; Majumdar, S.; Zaidi, S.A.; Ondachi, P.; McCorvy, J.D.; Wang, S.; Mosier, P.D.; Uprety, R.; Vardy, E.; Krumm, B.E.; et al. Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell 2018, 172, 55–67.e15. [Google Scholar] [CrossRef]
- Koehl, A.; Hu, H.; Maeda, S.; Zhang, Y.; Qu, Q.; Paggi, J.M.; Latorraca, N.R.; Hilger, D.; Dawson, R.; Matile, H.; et al. Structure of the micro-opioid receptor-Gi protein complex. Nature 2018, 558, 547–552. [Google Scholar] [CrossRef]
- Gmeiner, P.; Wang, H.; Hetzer, F.; Huang, W.; Qu, Q.; Meyerowitz, J.; Kaindl, J.; Hubner, H.; Skiniotis, G.; Kobilka, B.K. Structure-based Evolution of G protein-biased mu-opioid Receptor Agonists. Angew. Chem. Int. Ed. Engl. 2022, 61, e202200269. [Google Scholar]
- Mafi, A.; Kim, S.K.; Goddard, W.A., 3rd. The atomistic level structure for the activated human kappa-opioid receptor bound to the full Gi protein and the MP1104 agonist. Proc. Natl. Acad. Sci. USA 2020, 117, 5836–5843. [Google Scholar] [CrossRef]
- Manglik, A.; Lin, H.; Aryal, D.K.; McCorvy, J.D.; Dengler, D.; Corder, G.; Levit, A.; Kling, R.C.; Bernat, V.; Hubner, H.; et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 2016, 537, 185–190. [Google Scholar] [CrossRef]
- Lyu, J.; Wang, S.; Balius, T.E.; Singh, I.; Levit, A.; Moroz, Y.S.; O’Meara, M.J.; Che, T.; Algaa, E.; Tolmachova, K.; et al. Ultra-large library docking for discovering new chemotypes. Nature 2019, 566, 224–229. [Google Scholar] [CrossRef]
- Stein, R.M.; Kang, H.J.; McCorvy, J.D.; Glatfelter, G.C.; Jones, A.J.; Che, T.; Slocum, S.; Huang, X.P.; Savych, O.; Moroz, Y.S.; et al. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature 2020, 579, 609–614. [Google Scholar] [CrossRef]
- Irwin, J.J.; Shoichet, B.K. ZINC--a free database of commercially available compounds for virtual screening. J. Chem Inf Model. 2005, 45, 177–182. [Google Scholar] [CrossRef] [PubMed]
- Sterling, T.; Irwin, J.J. ZINC 15--Ligand Discovery for Everyone. J. Chem. Inf. Model. 2015, 55, 2324–2337. [Google Scholar] [CrossRef] [PubMed]
- Irwin, J.J.; Tang, K.G.; Young, J.; Dandarchuluun, C.; Wong, B.R.; Khurelbaatar, M.; Moroz, Y.S.; Mayfield, J.; Sayle, R.A. ZINC20-A Free Ultralarge-Scale Chemical Database for Ligand Discovery. J. Chem. Inf. Model. 2020, 60, 6065–6073. [Google Scholar] [CrossRef]
- Sadybekov, A.A.; Sadybekov, A.V.; Liu, Y.; Iliopoulos-Tsoutsouvas, C.; Huang, X.P.; Pickett, J.; Houser, B.; Patel, N.; Tran, N.K.; Tong, F.; et al. Synthon-based ligand discovery in virtual libraries of over 11 billion compounds. Nature 2022, 601, 452–459. [Google Scholar] [CrossRef] [PubMed]
- Seyedabadi, M.; Gharghabi, M.; Gurevich, E.V.; Gurevich, V.V. Structural basis of GPCR coupling to distinct signal transducers: Implications for biased signaling. Trends Biochem. Sci. 2022, 47, 570–581. [Google Scholar] [CrossRef] [PubMed]
- Huang, W.; Manglik, A.; Venkatakrishnan, A.J.; Laeremans, T.; Feinberg, E.N.; Sanborn, A.L.; Kato, H.E.; Livingston, K.E.; Thorsen, T.S.; Kling, R.C.; et al. Structural insights into micro-opioid receptor activation. Nature 2015, 524, 315–321. [Google Scholar] [CrossRef]
- Qu, Q.; Huang, W.; Aydin, D.; Paggi, J.M.; Seven, A.B.; Wang, H.; Chakraborty, S.; Che, T.; DiBerto, J.F.; Robertson, M.J.; et al. Structural insights into distinct signaling profiles of the μOR activated by diverse agonists. bioRxiv 2021. [Google Scholar] [CrossRef]
- Uprety, R.; Che, T.; Zaidi, S.A.; Grinnell, S.G.; Varga, B.R.; Faouzi, A.; Slocum, S.T.; Allaoa, A.; Varadi, A.; Nelson, M.; et al. Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site. Elife 2021, 10, e56519. [Google Scholar] [CrossRef]
- de Waal, P.W.; Shi, J.; You, E.; Wang, X.; Melcher, K.; Jiang, Y.; Xu, H.E.; Dickson, B.M. Molecular mechanisms of fentanyl mediated beta-arrestin biased signaling. PLoS Comput. Biol. 2020, 16, e1007394. [Google Scholar] [CrossRef]
- Pandy-Szekeres, G.; Esguerra, M.; Hauser, A.S.; Caroli, J.; Munk, C.; Pilger, S.; Keseru, G.M.; Kooistra, A.J.; Gloriam, D.E. The G protein database, GproteinDb. Nucleic Acids Res. 2022, 50, D518–D525. [Google Scholar] [CrossRef]
- Minnich, A.J.; McLoughlin, K.; Tse, M.; Deng, J.; Weber, A.; Murad, N.; Madej, B.D.; Ramsundar, B.; Rush, T.; Calad-Thomson, S.; et al. AMPL: A Data-Driven Modeling Pipeline for Drug Discovery. J. Chem. Inf. Model. 2020, 60, 1955–1968. [Google Scholar] [CrossRef] [PubMed]
- Jumper, J.; Evans, R.; Pritzel, A.; Green, T.; Figurnov, M.; Ronneberger, O.; Tunyasuvunakool, K.; Bates, R.; Zidek, A.; Potapenko, A.; et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021, 596, 583–589. [Google Scholar] [CrossRef] [PubMed]
- Callaway, E. What’s next for AlphaFold and the AI protein-folding revolution. Nature 2022, 604, 234–238. [Google Scholar] [CrossRef] [PubMed]
- Unke, O.T.; Chmiela, S.; Sauceda, H.E.; Gastegger, M.; Poltavsky, I.; Schutt, K.T.; Tkatchenko, A.; Muller, K.R. Machine Learning Force Fields. Chem Rev. 2021, 121, 10142–10186. [Google Scholar] [CrossRef]
- Doerr, S.; Majewski, M.; Perez, A.; Kramer, A.; Clementi, C.; Noe, F.; Giorgino, T.; De Fabritiis, G. TorchMD: A Deep Learning Framework for Molecular Simulations. J. Chem. Theory Comput. 2021, 17, 2355–2363. [Google Scholar] [CrossRef]
- Yang, Y.; Jimenez-Negron, O.A.; Kitchin, J.R. Machine-learning accelerated geometry optimization in molecular simulation. J. Chem. Phys. 2021, 154, 234704. [Google Scholar] [CrossRef]
- Fonseca, G.; Poltavsky, I.; Vassilev-Galindo, V.; Tkatchenko, A. Improving molecular force fields across configurational space by combining supervised and unsupervised machine learning. J. Chem. Phys. 2021, 154, 124102. [Google Scholar] [CrossRef]
- Guedes, I.A.; Pereira, F.S.S.; Dardenne, L.E. Empirical Scoring Functions for Structure-Based Virtual Screening: Applications, Critical Aspects, and Challenges. Front. Pharmacol. 2018, 9, 1089. [Google Scholar] [CrossRef]
- Jiménez-Luna, J.; Grisoni, F.; Schneider, G. Drug discovery with explainable artificial intelligence. Nat. Mach. Intell. 2020, 2, 573–584. [Google Scholar] [CrossRef]
Structure | Auxiliary Protein | Structure Ligand | |||||||
---|---|---|---|---|---|---|---|---|---|
Method | PDB | Resolution | State | Degree Active (%) | % of Seq | Fusion | Name | Type | Function |
X-ray | 6PT2 | 2.8 | Active | 76 | 78 | BRIL | KGCHM07 | peptide | Agonist |
X-ray | 6PT3 | 3.3 | Active | 76 | 78 | BRIL | DPI-287 | small-molecule | Agonist |
X-ray * | 4RWD | 2.7 | Inactive | 7 | 79 | BRIL | DIPP-NH2 | peptide | Antagonist |
X-ray | 4RWA | 3.3 | Inactive | 7 | 77 | BRIL | DIPP-NH2 | peptide | Antagonist |
X-ray | 4N6H | 1.8 | Inactive | 7 | 81 | BRIL | Naltrindole | small-molecule | Antagonist |
X-ray | 4EJ4 | 3.4 | Inactive | 7 | 76 | T4-Lysozyme | Naltrindole | small-molecule | Antagonist |
Agonist | Antagonist | ||||||||
---|---|---|---|---|---|---|---|---|---|
6PT2 | 6PT3 | 4RWD | 4RWA | 4N6H | 4EJ4 | ||||
Amino Acid | Sequence Number | Generic Number | Segment | KGCHM07 | DPI-287 | DIPP-NH2 | Naltrindole | ||
A | 98 | 2.53 | TM2 | ||||||
L | 125 | 3.29 | TM3 | ||||||
D | 128 | 3.32 | TM3 | ||||||
Y | 129 | 3.33 | TM3 | ||||||
M | 132 | 3.36 | TM3 | ||||||
M | 199 | ECL2 | ECL2 | ||||||
L | 200 | ECL2 | ECL2 | ||||||
D | 210 | 5.35 | TM5 | ||||||
K | 214 | 5.39 | TM5 | ||||||
V | 217 | 5.42 | TM5 | ||||||
W | 274 | 6.48 | TM6 | ||||||
I | 277 | 6.51 | TM6 | ||||||
H | 278 | 6.52 | TM6 | ||||||
V | 281 | 6.55 | TM6 | ||||||
W | 284 | 6.58 | TM6 | ||||||
R | 291 | ECL3 | ECL3 | ||||||
L | 300 | 7.35 | TM7 | ||||||
I | 304 | 7.39 | TM7 | ||||||
Y | 308 | 7.43 | TM7 | ||||||
Color legend: | Hydrophobic | Aromatic (face to edge) | Aromatic (face to face) | Accessible | |||||
polar (charge-assisted hydrogen bond) | polar (charge-charge) | polar (hydrogen bond) | polar (hydrogen bond with backbone) |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Meqbil, Y.J.; van Rijn, R.M. Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors. Pharmaceuticals 2022, 15, 873. https://doi.org/10.3390/ph15070873
Meqbil YJ, van Rijn RM. Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors. Pharmaceuticals. 2022; 15(7):873. https://doi.org/10.3390/ph15070873
Chicago/Turabian StyleMeqbil, Yazan J., and Richard M. van Rijn. 2022. "Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors" Pharmaceuticals 15, no. 7: 873. https://doi.org/10.3390/ph15070873
APA StyleMeqbil, Y. J., & van Rijn, R. M. (2022). Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors. Pharmaceuticals, 15(7), 873. https://doi.org/10.3390/ph15070873