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Salt bridge: key interaction between antipsychotics and receptors

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Abstract

Schizophrenia is a common psychiatric disorder that affects people’s thinking, feelings and behavior. One treatment of choice is the use of antipsychotic drugs. The mechanism of action of antipsychotics is one of the first topics of study needed to design new and more effective drugs. The main idea of this investigation is to analyze the salt bridge that is formed between antipsychotics and receptors. To model the salt bridge, we use different amines and acetate to represent Asp 3.32. For these systems, we found a linear correlation between the bond distance and the salt bridge interaction energy [E(SB)]. This correlation is then used to obtain the E(SB) of the ligands (antipsychotics and neurotransmitters) that interact with the receptors. The percentage of E(SB) with respect to total interaction energy is greater than 50%. This supports the idea that salt bridge is a key interaction. E(SB) is closely related to the ability to accept electrons, which was reported to be important for the activity of these drugs. With these results, we gain more insight into the interaction mechanism of antipsychotics with the corresponding receptors.

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References

  1. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Bäckers L, Rothe P, Cipriani A, Davis J, Salanti G, Leucht S (2019) Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. The Lancet 394:939–951. https://doi.org/10.1016/S0140-6736(19)31135-3

    Article  CAS  Google Scholar 

  2. Chokhawala K, Stevens L (2022) Antipsychotic medications StatPearls. Treasure Island. https://www.ncbi.nlm.nih.gov/books/NBK519503/

  3. Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, McGrath JJ, Whiteford HA (2018) Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016. Schizophr Bull 44:1195–1203. https://doi.org/10.1093/schbul/sby058

    Article  PubMed  PubMed Central  Google Scholar 

  4. Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G, Marder SR (2003) Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 60:681. https://doi.org/10.1001/archpsyc.60.7.681

  5. Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302:381–389. https://doi.org/10.1124/jpet.102.033175

    Article  CAS  PubMed  Google Scholar 

  6. Li P, Snyder LG, Vanover EK (2016) Dopamine targeting drugs for the treatment of schizophrenia: past, present and future. CTMC 16:3385–3403. https://doi.org/10.2174/1568026616666160608084834

    Article  CAS  Google Scholar 

  7. Wickelgren I (1998) A new route to treating schizophrenia? Science 281:1264–1265. https://doi.org/10.1371/journal.pone.0224691

    Article  CAS  PubMed  Google Scholar 

  8. Marino MJ, Knutsen LJS, Williams M (2008) Emerging opportunities for antipsychotic drug discovery in the postgenomic era. J Med Chem 51:1077–1107. https://doi.org/10.2174/1568026616666160608084834

    Article  CAS  PubMed  Google Scholar 

  9. Forray C, Buller R (2017) Challenges and opportunities for the development of new antipsychotic drugs. Biochem Pharmacol 143:10–24. https://doi.org/10.1016/j.bcp.2017.05.009

    Article  CAS  PubMed  Google Scholar 

  10. Delay J, Deniker P, Harl MJ (1952) Traitement des états d’excitation et d’agitation par une méthode médicamenteuse dérivée de l’hibernithérapie. Ann Med Psychol 110:267–273

    CAS  Google Scholar 

  11. Chauhan A, Mittal A, Arora PK (2013) Typical antipsychotics from scratch to the present. J Pharm Sci Res 4:184–204

    Google Scholar 

  12. Mauri MC, Paletta S, Maffini M, Colasanti A, Dragogna F, Di Pace C, Altamura AC (2014) Clinical pharmacology of atypical antipsychotics: an update. EXCLI J 13:1163–1191

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: A new hypothesis. AJP 158:360–369

    Article  CAS  Google Scholar 

  14. Geddes J, Freemantle N, Harrison P, Bebbington P (2000) Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 321:1371–1376. https://doi.org/10.1136/bmj.321.7273.1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ananth J, Burgoyne KS, Gadasalli R, Aquino S (2001) How do the atypical antipsychotics work? J Psychiatry Neurosci 26:385–394

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Seeman P (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47:27–38. https://doi.org/10.1177/070674370204700106

    Article  PubMed  Google Scholar 

  17. Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, Höschk C (2006) Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 20:389–409. https://doi.org/10.2165/00023210-200620050-00004

    Article  CAS  PubMed  Google Scholar 

  18. Miyamoto S, Duncan GE, Marx CE, Lieberman JA (2004) Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 10:79–104. https://doi.org/10.1038/sj.mp.4001556

    Article  CAS  Google Scholar 

  19. Stahl SM, Shayegan DK (2003) The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry 64:6–12

    PubMed  Google Scholar 

  20. Stępnicki P, Kondej M, Kaczor AA (2018) Current concepts and treatments of schizophrenia. Molecules 23:2087. https://doi.org/10.3390/molecules23082087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Laborit H, Huguenard P, Aullaume R (1952) Un nouveau stabilisateur végétatif (le 4560 R.P.). Press Méd 60:206–208

    CAS  PubMed  Google Scholar 

  22. López-Muñoz F, Álamo C, Cuenca E, Shen WW, Clervoy P, Rubio G (2005) History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry 17:113–135. https://doi.org/10.1080/10401230591002002

    Article  PubMed  Google Scholar 

  23. Mitchell P (1993) Chlorpromazine turns forty. Aust N Z J Psychiatry 27:370–373

    Article  CAS  PubMed  Google Scholar 

  24. Rosenbloom M (2002) Chlorpromazine and the psychopharmacologic revolution. JAMA 287:1860. https://doi.org/10.1001/jama.287.14.1860-JMS0410-6-1

  25. Boyd-Kimball D, Gonczy K, Lewis B et al (2018) Classics in chemical neuroscience: chlorpromazine. ACS Chem Neurosci 10:79–88. https://doi.org/10.1021/acschemneuro.8b00258

    Article  CAS  PubMed  Google Scholar 

  26. Meltzer HY, Bastani B, Ramirez L, Matsubara S (1989) Clozapine: new research on efficacy and mechanism of action. Eur Arch Psychiatr Neurol Sci 238:332–339. https://doi.org/10.1007/BF00449814

    Article  CAS  Google Scholar 

  27. Wenthur CJ, Lindsley CW (2013) Classics in chemical neuroscience: clozapine. ACS Chem Neurosci 4:1018–1025. https://doi.org/10.1021/cn400121z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Seeman P (2013) Clozapine, a fast-Off-D2 antipsychotic. ACS Chem Neurosci 5:24–29. https://doi.org/10.1021/cn400189s

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chopko TC, Lindsley CW (2018) Classics in chemical neuroscience: risperidone. ACS Chem Neurosci 9:1520–1529. https://doi.org/10.1021/acschemneuro.8b00159

    Article  CAS  PubMed  Google Scholar 

  30. Tyler MW, Zaldivar-Diez J, Haggarty SJ (2017) Classics in chemical neuroscience: haloperidol. ACS Chem Neurosci 8:444–453. https://doi.org/10.1021/cn400189s

    Article  CAS  PubMed  Google Scholar 

  31. Martínez A, Vargas R (2018) A component of the puzzle, when attempting to understand antipsychotics: a theoretical study of chemical reactivity indexes. JPPR 1:1–8

    Google Scholar 

  32. Castillo RM, Ramos E, Martínez A (2020) Interaction of graphene with antipsychotic drugs: is there any charge transfer process? J Comput Chem 42:60–65. https://doi.org/10.1002/jcc.26433

    Article  CAS  PubMed  Google Scholar 

  33. Martínez A, Ibarra IA, Vargas R (2019) A quantum chemical approach representing a new perspective concerning agonist and antagonist drugs in the context of schizophrenia and Parkinson’s disease. PLoS One 14:e0224691. https://doi.org/10.1371/journal.pone.0224691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Martinez A (2020) Dopamine antagonists for the treatment of drug addiction: PF-4363467 and related compounds. Eur J Chem 11:84–90. https://doi.org/10.5155/eurjchem.11.1.84-90.1970

    Article  CAS  Google Scholar 

  35. Goode-Romero G, Winnberg U, Domínguez L et al (2020) New information of dopaminergic agents based on quantum chemistry calculations. Sci Rep. https://doi.org/10.1038/s41598-020-78446-4

    Article  PubMed  PubMed Central  Google Scholar 

  36. Goode-Romero G, Dominguez L, Vargas R, Ibarra IA, Martínez A (2021) Analyzing the interaction energy between dopaminergic agents and DRD2: is there any difference between risperidone (antagonist), aripiprazole (partial agonist) and pramipexole (agonist)? Comput Theor Chem 1197:113–125. https://doi.org/10.1016/j.comptc.2020.113125

    Article  CAS  Google Scholar 

  37. Martínez A (2021) Electron donor-acceptor capacity of selected pharmaceuticals against COVID-19. Antioxidants 10:979. https://doi.org/10.3390/antiox10060979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pylaeva S, Brehm M, Sebastiani D (2018) Salt bridge in aqueous solution: strong structural motifs but weak enthalpic effect. Sci Rep. https://doi.org/10.1038/s41598-018-31935-z

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kurczab R, Śliwa P, Rataj K et al (2018) Salt Bridge in Ligand-Protein Complexes—Systematic theoretical and statistical investigations. J Chem Inf Model 58:2224–2238. https://doi.org/10.1021/acs.jcim.8b00266

    Article  CAS  PubMed  Google Scholar 

  40. Kalani MYS, Vaidehi N, Hall SE et al (2004) The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists. Proc Natl Acad Sci USA 101:3815–3820. https://doi.org/10.1073/pnas.0400100101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stewart JJP (2012) Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and re-optimization of parameters. J Mol Model 19:1–32. https://doi.org/10.1007/s00894-012-1667-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Klamt A, Schüürmann G (1993) COSMO: a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient. J Chem Soc Perkin Trans 2:799–805. https://doi.org/10.1039/P29930000799

    Article  Google Scholar 

  43. Perdew JP, Ernzerhof M, Burke K (1996) Rationale for mixing exact exchange with density functional approximations. J Chem Phys 105:9982–9985. https://doi.org/10.1063/1.472933

    Article  CAS  Google Scholar 

  44. Adamo C, Barone V (1999) Toward reliable density functional methods without adjustable parameters: the PBE0 model. J Chem Phys 110:6158–6170. https://doi.org/10.1063/1.478522

    Article  CAS  Google Scholar 

  45. Ernzerhof M, Scuseria GE (1999) Assessment of the Perdew–Burke–Ernzerhof exchange-correlation functional. J Chem Phys 110:5029–5036. https://doi.org/10.1063/1.478401

    Article  CAS  Google Scholar 

  46. Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H–Pu. J Chem Phys 132:154104. https://doi.org/10.1063/1.3382344

    Article  CAS  PubMed  Google Scholar 

  47. Krishnan R, Binkley JS, Seeger R, Pople JA (1980) Self-consistent molecular orbital methods. XX. A basis set for correlated wave functions. J Chem Phys 72:650–654. https://doi.org/10.1063/1.438955

    Article  CAS  Google Scholar 

  48. McLean AD, Chandler GS (1980) Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z = 11–18. J Chem Phys 72:5639–5648. https://doi.org/10.1063/1.438980

    Article  CAS  Google Scholar 

  49. García-Gutiérrez P, Zubillaga RA, Ibarra IA, Martínez A, Vargas R, Garza J (2021) Non-conventional interactions of N3 inhibitor with the main protease of SARS-CoV and SARS-CoV-2. CSBJ 19:4669–4675. https://doi.org/10.1016/j.csbj.2021.08.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bader RFW (1990) Atoms in molecules: a quantum theory. International series of monographs on chemistry. Clarendon Press

    Google Scholar 

  51. Grabowski SJ (2011) What is the covalency of hydrogen bonding? Chem Rev 111:2597–2625. https://doi.org/10.1021/cr800346f

    Article  CAS  PubMed  Google Scholar 

  52. Stewart JJP (2018) MOPAC2016. Stewart Computational Chemistry, Colorado Springs. http://openmopac.net/

  53. Ufimtsev IS, Martínez TJ (2008) Quantum chemistry on graphical processing units. 1. Strategies for two-electron integral evaluation. J Chem Theory Comput 4:222–231. https://doi.org/10.1021/ct700268q

    Article  CAS  PubMed  Google Scholar 

  54. Ufimtsev IS, Martinez TJ (2009) Quantum chemistry on graphical processing units. 2. Direct self-consistent-field implementation. J Chem Theory Comput 5:1004–1015. https://doi.org/10.1021/ct800526s

    Article  CAS  PubMed  Google Scholar 

  55. Ufimtsev IS, Martinez TJ (2009) Quantum chemistry on graphical processing units. 3. Analytical energy gradients, geometry optimization, and first principles molecular dynamics. J Chem Theory Comput 5:2619–2628. https://doi.org/10.1021/ct9003004

    Article  CAS  PubMed  Google Scholar 

  56. Søndergaard CR, Olsson MHM, Rostkowski M, Jensen JH (2011) Improved treatment of ligands and coupling effects in empirical calculation and rationalization of pKa values. J Chem Theory Comput 7:2284–2295. https://doi.org/10.1021/ct200133y

    Article  CAS  PubMed  Google Scholar 

  57. Olsson MHM, Søndergaard CR, Rostkowski M, Jensen JH (2011) PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J Chem Theory Comput 7:525–537. https://doi.org/10.1021/ct100578z

    Article  CAS  PubMed  Google Scholar 

  58. Garza J, Ramírez J-Z, Vargas R (2005) Role of Hartree−Fock and Kohn−Sham orbitals in the basis set superposition error for systems linked by hydrogen bonds. J Phys Chem A 109:643–651. https://doi.org/10.1021/jp046492+

    Article  CAS  PubMed  Google Scholar 

  59. Gázquez JL, Cedillo A, Vela A (2007) Electrodonating and electroaccepting powers. J Phys Chem A 111:1966–1970. https://doi.org/10.1021/jp065459f

    Article  CAS  PubMed  Google Scholar 

  60. Gázquez JL (2008) Perspectives on the density functional theory of chemical reactivity. J Mex Chem Soc 52:3–10

    Google Scholar 

  61. Martínez A, Rodríguez-Gironés MA, Barbosa A, Costas M (2008) Donator acceptor map for carotenoids, melatonin and vitamins. J Phys Chem A 112:9037–9042. https://doi.org/10.1021/jp803218e

    Article  CAS  PubMed  Google Scholar 

  62. Martínez A (2009) Donator acceptor map of psittacofulvins and anthocyanins: are they good antioxidant substances? J Phys Chem B 113:4915–4921. https://doi.org/10.1021/jp8102436

    Article  CAS  PubMed  Google Scholar 

  63. Martínez A (2020) Cloroquine and hydroxychloroquine: the Yin-yang of these drugs from a theoretical study. J Mex Chem Soc. https://doi.org/10.29356/jmcs.v64i3.1213

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Acknowledgements

This article is dedicated to Professor Pratim Kumar Chatarraj who has contributed substantially to the development of the Conceptual DFT; happy 65th anniversary. We thank to the Laboratorio de Supercómputo y Visualización en Paralelo at the Universidad Autónoma Metropolitana-Iztapalapa for access to their computer facilities. Ana Martínez thanks to LANCAD-UNAM-DGTIC-141. Gerardo Padilla-Bernal thanks to CONACYT for scholarship 774374. We also thank Dr. Raymundo Hernández-Esparza for fruitful discussions and guidance in the use of semiempirical methods.

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  1. División de Ciencias Básicas e Ingeniería, Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, Iztapalapa. AP Postal 55-534, CP 09340, CDMX, México

    Gerardo Padilla-Bernal & Rubicelia Vargas

  2. Departamento de Materiales de Baja Dimensionalidad. Instituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Exterior S. N., Ciudad Universitaria, CP 04510, CDMX, México

    Ana Martínez

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  1. Gerardo Padilla-Bernal
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Correspondence to Rubicelia Vargas.

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Padilla-Bernal, G., Vargas, R. & Martínez, A. Salt bridge: key interaction between antipsychotics and receptors. Theor Chem Acc 142, 65 (2023). https://doi.org/10.1007/s00214-023-03016-6

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