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DFT, ADME studies and evaluation of the binding with HSA and MAO-B inhibitory potential of protoberberine alkaloids from Guatteria friesiana: theoretical insights of promising candidates for the treatment of Parkinson’s disease

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Abstract

Context

Parkinson’s disease is a chronic neurodegenerative condition that has no cure, characterized by the progressive degeneration of specific brain cells responsible for producing dopamine, a crucial neurotransmitter for controlling movement and muscle coordination. Parkinson’s disease is estimated to affect around 1% of the world’s population over the age of 60, but it can be diagnosed at younger ages. One of the treatment strategies for Parkinson’s disease involves the use of drugs that aim to increase dopamine levels or simulate the action of dopamine in the brain. A class of commonly prescribed drugs are the so-called monoamine oxidase B (MAO-B) inhibitors due to the fact that this enzyme is responsible for metabolizing dopamine, thus reducing its levels in the brain. Studies have shown that berberine-derived alkaloids have the ability to selectively inhibit MAO-B activity, resulting in increased dopamine availability in the brain. In this context, berberine derivatives 13-hydroxy-discretinine and 7,8-dihydro-8-hydroxypalmatine, isolated from Guatteria friesiana, were evaluated via density functional theory followed by ADME studies, docking and molecular dynamic simulations with MAO-B, aiming to evaluate their anti-Parkinson potential, which have not been reported yet. Docking simulations with HSA were carried out aiming to evaluate the transport of these molecules through the circulatory system.

Methods

The 3D structures of the berberine-derived alkaloids were modeled via the DFT approach at B3LYP-D3(BJ)/6–311 + + G(2df, 2pd) theory level using Gaussian 09 software. Solvation free energies were determined through Truhlar’s solvation model. MEP and ALIE maps were generated with Multiwfn software. Autodock Vina software was used for molecular docking simulations and analysis of the interactions in the binding sites. The 3D structure of MAO-B was obtained from the Protein Data Bank website under PDB code 2V5Z. For the interaction of studied alkaloids with human serum albumin (HSA) drug sites, 3D structures with PDB codes 2BXD, 2BXG, and 4L9K were used. Molecular dynamics simulations were carried out using GROMACS 2019.4 software, with the GROMOS 53A6 force field at 100 ns simulation time. The estimation of the ligand’s binding free energies was obtained via molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method.

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Further information regarding this study will be provided upon request.

References

  1. Alexander GE (2004) Biology of Parkinson’s disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder. Dialogues Clin Neurosci 6:259–280. https://doi.org/10.31887/dcns.2004.6.3/galexander

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rizek P, Kumar N, Jog MS (2016) An update on the diagnosis and treatment of Parkinson disease. CMAJ 188:1157–1165. https://doi.org/10.1503/cmaj.151179

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sveinbjornsdottir S (2016) The clinical symptoms of Parkinson’s disease. J Neurochem 139:318–324. https://doi.org/10.1111/jnc.13691

    Article  CAS  PubMed  Google Scholar 

  4. Gaba S, Saini A, Singh G, Monga V (2021) An insight into the medicinal attributes of berberine derivatives: a review. Bioorg Med Chem 38:116143. https://doi.org/10.1016/j.bmc.2021.116143

    Article  CAS  PubMed  Google Scholar 

  5. Kong Y, Li L, Zhao L-G, Yu P, Li D-D (2021) A patent review of berberine and its derivatives with various pharmacological activities (2016–2020). Expert Opin Ther Pat 32:211–223. https://doi.org/10.1080/13543776.2021.1974001

    Article  CAS  PubMed  Google Scholar 

  6. Singh AK, Singh SK, Nandi MK, Mishra G, Maurya A, Rai A, Kai GP, Awasthi R, Sharma B, Kulkarni G (2019) Berberine: a plant-derived alkaloid with therapeutic potential to combat Alzheimer’s disease. Cent Nerv Syst Agents Med Chem 19:154–170. https://doi.org/10.2174/1871524919666190820160053

    Article  CAS  PubMed  Google Scholar 

  7. Ribaudo G, Zanforlin E, Canton M, Bova S, Zagotto G (2017) Preliminary studies of berberine and its semi-synthetic derivatives as a promising class of multi-target anti-parkinson agents. Nat Prod Res 32:1395–1401. https://doi.org/10.1080/14786419.2017.1350669

    Article  CAS  PubMed  Google Scholar 

  8. Sawada H, Oeda T, Yamamoto K (2013) Catecholamines and neurodegeneration in Parkinson’s disease—from diagnostic marker to aggregations of α-synuclein. Diagnostics 3:210–221. https://doi.org/10.3390/diagnostics3020210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Costa EV, da Cruz PEO, Pinheiro MLB, Marques FA, Ruiz ALTG, Marchetti GM, Carvalho JE, Barison A, Maia BHLNS (2013) Aporphine and tetrahydroprotoberberine alkaloids from the leaves of Guatteria friesiana (Annonaceae) and their cytotoxic activities. J Braz Chem Soc 24:788–796. https://doi.org/10.5935/0103-5053.20130103

    Article  CAS  Google Scholar 

  10. Costa EV, Pinheiro MLB, Barison A, Campos FR, Salvador MJ, Maia BH, Cabral EC, Eberlin MN (2010) Alkaloids from the bark of Guatteria hispida and their evaluation as antioxidant and antimicrobial agents. J Nat Prod 73:1180–1183. https://doi.org/10.1021/np100013r

    Article  CAS  PubMed  Google Scholar 

  11. Tayyab S, Feroz SR (2021) Serum albumin: clinical significance of drug binding and development as drug delivery vehicle. Adv Protein Chem Struct Biol 123:193–218. https://doi.org/10.1016/bs.apcsb.2020.08.003

    Article  CAS  PubMed  Google Scholar 

  12. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JAJr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ. Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford CT, (2016)

  13. Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 113:6378–6396. https://doi.org/10.1021/jp810292n

    Article  CAS  PubMed  Google Scholar 

  14. Lu T, Chen F (2011) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33:580–592. https://doi.org/10.1002/jcc.22885

    Article  CAS  PubMed  Google Scholar 

  15. Trott O, Olson AJ (2009) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461. https://doi.org/10.1002/jcc.21334

    Article  CAS  Google Scholar 

  16. Binda C, Wang J, Pisani L, Caccia C, Carotti A, Salvati P, Edmondson DE, Mattevi A (2007) Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J Med Chem 50:5848–5852. https://doi.org/10.1021/jm070677y

    Article  CAS  PubMed  Google Scholar 

  17. Ghuman J, Zunszain PA, Petitpas I, Bhattacharya AA, Otagiri M, Curry S (2005) Structural basis of the drug-binding specificity of human serum albumin. J Mol Bio 353:38–52. https://doi.org/10.1016/j.jmb.2005.07.075

    Article  CAS  Google Scholar 

  18. Wang Z, Ho JX, Ruble JR, Rose J, Rüker F, Ellenburg M, Murphy R, Click J, Soistman E, Wilkerson L, Carter DC (2013) Structural studies of several clinically important oncology drugs in complex with human serum albumin. Biochim Biophys Acta 1830:5356–5374. https://doi.org/10.1016/j.bbagen.2013.06.032

    Article  CAS  PubMed  Google Scholar 

  19. Lemkul JA, Allen WJ, Bevan DR (2010) Practical considerations for building GROMOS-compatible small-molecule topologies. J Chem Inf Model 50:2221–2235. https://doi.org/10.1021/ci100335w

    Article  CAS  PubMed  Google Scholar 

  20. van Aalten DMFRP, Bywater FJBC, Hendlich M, Hooft RWW, Vriend G (1996) PRODRG, a program for generating molecular topologies and unique molecular descriptors from coordinates of small molecules. J Comput-aided Mol Des 10:255–262. https://doi.org/10.1007/bf00355047

    Article  PubMed  Google Scholar 

  21. Kumari R, Kumar R, Lynn A (2014) g_mmpbsa—a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54:1951–1962. https://doi.org/10.1021/ci500020m

    Article  CAS  PubMed  Google Scholar 

  22. Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717. https://doi.org/10.1038/srep42717

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhuo L-G, Liao W, Yu Z-X (2012) a frontier molecular orbital theory approach to understanding the mayr equation and to quantifying nucleophilicity and electrophilicity by using HOMO and LUMO energies. Asian J Org Chem 1:336–345. https://doi.org/10.1002/ajoc.201200103

    Article  CAS  Google Scholar 

  24. Yu J, Su NQ, Yang W (2022) Describing chemical reactivity with frontier molecular orbitalets. JACS Au 2:1383–1394. https://doi.org/10.1021/jacsau.2c00085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Domingo LR, Pérez P (2011) The nucleophilicity N index in organic chemistry. Org Biomol Chem 9:7168–7175. https://doi.org/10.1039/c1ob05856h

    Article  CAS  PubMed  Google Scholar 

  26. Costa RA, Junior ESA, Lopes GBP, Pinheiro MLB, Costa EV, Bezerra DP, Oliveira K (2018) Structural, vibrational, UV–vis, quantum-chemical properties, molecular docking and anti-cancer activity study of annomontine and N-hydroxyannomontine β-carboline alkaloids: a combined experimental and DFT approach. J Mol Struct 1171:682–695. https://doi.org/10.1016/j.molstruc.2018.06.054

    Article  CAS  Google Scholar 

  27. Lone SH, Jameel S, Bhat MA, Lone RA, Butcher RJ, Bhat KA (2018) Synthesis of an unusual quinazoline alkaloid: theoretical and experimental investigations of its structural, electronic, molecular and biological properties. RSC Adv 8:8259–8268. https://doi.org/10.1039/c8ra00138c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Thomas R, Hossain M, Mary YS, Resmi KS, Armaković S, Armaković SJ, Nanda AK, Ranjan VK, Vijayakumar G, Alsenoy CV (2018) Spectroscopic analysis and molecular docking of imidazole derivatives and investigation of its reactive properties by DFT and molecular dynamics simulations. J Mol Struct 1158:156–175. https://doi.org/10.1016/j.molstruc.2018.01.021

    Article  CAS  Google Scholar 

  29. Sjoberg P, Politzer P (1990) Use of the electrostatic potential at the molecular surface to interpret and predict nucleophilic processes. J Phys Chem 94:3959–3961. https://doi.org/10.1021/j100373a017

    Article  CAS  Google Scholar 

  30. Murray JS, Sen K (1996) Molecular electrostatic potentials: concepts and applications. Elsevier Sci 3:1137

    Google Scholar 

  31. Costa RA, da Silva JN, Oliveira VG, Anselmo LM, Araújo MM, Oliveira KMT, Nunomura RCS (2021) New insights into structural, electronic, reactivity, spectroscopic and pharmacological properties of Bergenin: experimental, DFT calculations, MD and docking simulations. J Mol Liq 330:115625. https://doi.org/10.1016/j.molliq.2021.115625

    Article  CAS  Google Scholar 

  32. Pucci R, Angilella GGN (2022) Density functional theory, chemical reactivity, and the Fukui functions. Found Chem 24:59–71. https://doi.org/10.1007/s10698-022-09416-z

    Article  CAS  Google Scholar 

  33. Fradera X, Solà M (2003) Second-order atomic Fukui indices from the electron-pair density in the framework of the atoms in molecules theory. J Comput Chem 25:439–446. https://doi.org/10.1002/jcc.10396

    Article  CAS  Google Scholar 

  34. Padmanabhan J, Parthasarathi R, Sarkar U, Subramanian V, Chattaraj PK (2004) Effect of solvation on the condensed Fukui function and the generalized philicity index. Chem Phys Lett 383:122–128. https://doi.org/10.1016/j.cplett.2003.11.013

    Article  CAS  Google Scholar 

  35. Martínez-Araya JI (2014) Why is the dual descriptor a more accurate local reactivity descriptor than Fukui functions? J Math Chem 53:451–465. https://doi.org/10.1007/s10910-014-0437-7

    Article  CAS  Google Scholar 

  36. Heyden M (2019) Disassembling solvation free energies into local contributions—toward a microscopic understanding of solvation processes. WIREs Comput Mol Sci 9:e1390. https://doi.org/10.1002/wcms.1390

  37. Duarte GRM, Kyu DY, Loeffler HH, Chodera JD, Shirts MR, Mobley DL (2017) Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the freesolv database. J Chem Amp Eng Data 62:1559–1569. https://doi.org/10.1021/acs.jced.7b00104

    Article  CAS  Google Scholar 

  38. Zhu D, Cheng H, Li J, Zhang W, Shen Y, Chen S, Ge Z, Chen S (2016) Enhanced water-solubility and antibacterial activity of novel chitosan derivatives modified with quaternary phosphonium salt. Mater Sci Eng C Mater Biol Appl 61:79–84. https://doi.org/10.1016/j.msec.2015.12.024

    Article  CAS  PubMed  Google Scholar 

  39. Savjani KT, Gajjar AK, Savjani JK (2012) Drug solubility: importance and enhancement techniques. ISRN Pharm 2012:1–10. https://doi.org/10.5402/2012/195727

    Article  CAS  Google Scholar 

  40. Ratrey P, Dalvi SV, Mishra A (2020) Enhancing aqueous solubility and antibacterial activity of curcumin by complexing with cell-penetrating octaarginine. ACS Omega 5:19004–19013. https://doi.org/10.1021/acsomega.0c02321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen Y, Li J, Li Q, Shen Y, Ge Z, Zhang W, Chen S (2016) Enhanced water-solubility, antibacterial activity and biocompatibility upon introducing sulfobetaine and quaternary ammonium to chitosan. Carbohydr Polym 143:246–253. https://doi.org/10.1016/j.carbpol.2016.01.073

    Article  CAS  PubMed  Google Scholar 

  42. Murugan NA, Zaleśny R (2020) Multiscale modeling of two-photon probes for Parkinson’s diagnostics based on monoamine oxidase B biomarker. J Chem Inf Model 60:3854–3863. https://doi.org/10.1021/acs.jcim.0c00423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sudlow G, Birkett DJ, Wade DN (1975) The characterization of two specific drug binding sites on human serum albumin. Mol Pharmacol 11:824–832

    CAS  PubMed  Google Scholar 

  44. Yamasaki K, Maruyama T, Kragh-Hansen U, Otagiri M (1996) Characterization of site I on human serum albumin: concept about the structure of a drug binding site. Biochim Biophys Acta 1295:147–157. https://doi.org/10.1016/0167-4838(96)00013-1

    Article  PubMed  Google Scholar 

  45. Wanwimolruk S, Birkett DJ, Brooks PM (1983) Structural requirements for drug binding to site II on human serum albumin. Mol Pharmacol 24:458–463

    CAS  PubMed  Google Scholar 

  46. Carter DC (2010) Crystallographic survey of albumin drug interaction and preliminary applications in cancer chemotherapy. In Burger’s Medicinal Chemistry, Drug Discovery and Development, pp 437−468. https://doi.org/10.1002/0471266949.bmc166

  47. Zsila F (2013) Subdomain IB is the third major drug binding region of human serum albumin: toward the three-sites model. Mol Pharm 10:1668–1682. https://doi.org/10.1021/mp400027q

    Article  CAS  PubMed  Google Scholar 

  48. Mishra V, Heath RJ (2021) Structural and biochemical features of human serum albumin essential for eukaryotic cell culture. Int J Mol Sci 22:8411–8411. https://doi.org/10.3390/ijms22168411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang C, Greene D, Xiao L, Qi R (2018) Recent developments and applications of the MMPBSA method. Front Mol Biosci 4:87. https://doi.org/10.3389/fmolb.2017.00087

  50. Hou T, Wang J, Li Y, Wang W (2011) Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations. J Chem Inf Model 51(1):69–82. https://doi.org/10.1021/ci100275a

    Article  CAS  PubMed  Google Scholar 

  51. Huang K, Luo S, Cong Y, Zhong S, Zhang JZH, Duan L (2020) An accurate free energy estimator: based on MM/PBSA combined with interaction entropy for protein–ligand binding affinity. Nanoscale 12:10737–10750. https://doi.org/10.1039/c9nr10638c

    Article  CAS  PubMed  Google Scholar 

  52. Penner N, Xu L, Prakash C (2012) Radiolabeled absorption, distribution, metabolism, and excretion studies in drug development: why, when, and how? Chem Res Toxicol 25:513–531. https://doi.org/10.1021/tx300050f

    Article  CAS  PubMed  Google Scholar 

  53. Vrbanac J, Slauter R (2017) Chapter 3 - ADME in drug discovery. In A Comprehensive Guide to Toxicology in Nonclinical Drug Development, 2nd edn. Boston: Acad Press, MA, pp 39–67. https://doi.org/10.1016/B978-0-12-803620-4.00003-7

  54. Pollastri MP (2010) Overview on the rule of five. Curr Protoc Pharmacol 49:12. https://doi.org/10.1002/0471141755.ph0912s49

    Article  Google Scholar 

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Funding

The authors are grateful to the Universidade Federal do Amazonas (UFAM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Finance Code 001, for financial support and fellowship of this study. J.S. Al-Otaibi expresses his gratitude to the Researchers Supporting Project No. (PNURSP2023R3) from Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

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Authors and Affiliations

  1. Department of Chemistry, Federal University of Amazonas (DQ-UFAM), Manaus, AM, 69080-900, Brazil

    Victor L. Tananta, Emmanoel V. Costa & Renyer A. Costa

  2. Thushara, Neethinagar-64, Kollam, Kerala, India

    Y. Sheena Mary & Y. Shyma Mary

  3. Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, P.O. Box 8442811671, Riyadh, Saudi Arabia

    Jamelah S.Al-Otaibi

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  1. Victor L. Tananta
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  5. Jamelah S.Al-Otaibi
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Contributions

Victor L. Tananta: conceptualization, software, data curation, validation, writing – original draft. Emmanoel V. Costa: investigation, writing – review and editing. J.S. Al-Otaibi, Y.Sheena Mary, Y. Shyma Mary: investigation, data curation, software, writing – review and editing. Renyer A. Costa: conceptualization, software, validation, supervision, writing – review and editing.

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Correspondence to Renyer A. Costa.

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Tananta, V.L., Costa, E.V., Mary, Y.S. et al. DFT, ADME studies and evaluation of the binding with HSA and MAO-B inhibitory potential of protoberberine alkaloids from Guatteria friesiana: theoretical insights of promising candidates for the treatment of Parkinson’s disease. J Mol Model 29, 353 (2023). https://doi.org/10.1007/s00894-023-05756-5

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