Evaluation of the Key Structural Features of Various Butyrylcholinesterase Inhibitors Using Simple Molecular Descriptors
Abstract
:1. Introduction
2. Materials and Methods
2.1. Calculation of Topological Indices
2.2. Scoring Functions
2.3. Regression Calculations
3. Results and Discussion
Interactions in BChE–Inhibitor Complexes
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
- Nicolet, Y.; Lockridge, O.; Masson, P.; Fontecilla-Camps, J.C.; Nachon, F. Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products. J. Biol. Chem. 2003, 278, 41141–41147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ngamelue, M.N.; Homma, K.; Lockridge, O.; Asojo, O.A. Crystallization and X-ray structure of full-length recombinant human butyrylcholinesterase. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 2007, 63, 723–727. [Google Scholar] [CrossRef] [PubMed]
- Rosenberry, T.L.; Brazzolotto, X.; MacDonald, I.R.; Wandhammer, M.; Trovaslet-Leroy, M.; Darvesh, S.; Nachon, F. Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase: A crystallographic, kinetic and calorimetric study. Molecules 2017, 22, 2098. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Giacobini, E. Cholinesterases in human brain: The effect of cholinesterase inhibitors on Alzheimer’s disease and related disorders. In The Brain Cholinergic System; CRC Press: Boca Raton, FL, USA, 2006; pp. 235–264. [Google Scholar] [CrossRef]
- Lockridge, O.; Norgren, R.B.; Johnson, R.C.; Blake, T.A. Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors. Chem. Res. Toxicol. 2016, 29, 1381–1392. [Google Scholar] [CrossRef] [PubMed]
- Gazić, I.; Bosak, A.; Šinko, G.; Vinković, V.; Kovarik, Z. Preparative HPLC separation of bambuterol enantiomers and stereoselective inhibition of human cholinesterases. Anal. Bioanal. Chem. 2006, 385, 1513–1519. [Google Scholar] [CrossRef] [PubMed]
- Reiner, E.; Sinko, G.; Skrinjarić-Spoljar, M.; Simeon-Rudolf, V. Comparison of protocols for measuring activities of human blood cholinesterases by the Ellman method. Arh. Hig. Rada Toksikol. 2000, 51, 13–18. [Google Scholar] [PubMed]
- Košak, U.; Strašek, N.; Knez, D.; Jukič, M.; Žakelj, S.; Zahirović, A.; Pišlar, A.; Brazzolotto, X.; Nachon, F.; Kos, J.; et al. N-alkylpiperidine carbamates as potential anti-Alzheimer’s agents. Eur. J. Med. Chem. 2020, 197, 112282. [Google Scholar] [CrossRef] [PubMed]
- Meden, A.; Knez, D.; Malikowska-Racia, N.; Brazzolotto, X.; Nachon, F.; Svete, J.; Sałat, K.; Grošelj, U.; Gobec, S. Structure-activity relationship study of tryptophan-based butyrylcholinesterase inhibitors. Eur. J. Med. Chem. 2020, 208, 112766. [Google Scholar] [CrossRef] [PubMed]
- Brimijoin, S.; Chen, V.P.; Pang, Y.-P.; Geng, L.; Gao, Y. Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis. Chem. Biol. Interact. 2016, 259, 271–275. [Google Scholar] [CrossRef] [PubMed]
- Gauthier, S.; Rosa-Neto, P.; Morais, J.A.; Webster, C. World Alzheimer Report 2021; Alzheimer’s Disease International: London, UK, 2021. [Google Scholar]
- Mesulam, M.-M.; Guillozet, A.; Shaw, P.; Levey, A.; Duysen, E.G.; Lockridge, O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 2002, 110, 627–639. [Google Scholar] [CrossRef]
- Agis-Torres, A.; Sollhuber, M.; Fernandez, M.; Sanchez-Montero, J.M. Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer’s Disease. Curr. Neuropharmacol. 2014, 12, 2–36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rullo, M.; Catto, M.; Carrieri, A.; de Candia, M.; Altomare, C.D.; Pisani, L. Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones. Molecules 2019, 24, 4507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Miličević, A.; Šinko, G. Use of connectivity index and simple topological parameters for estimating the inhibition potency of acetylcholinesterase. Saudi Pharm. J. 2022, 30, 369–376. [Google Scholar] [CrossRef] [PubMed]
- Rossi, M.; Freschi, M.; de Camargo Nascente, L.; Salerno, A.; de Melo Viana Teixeira, S.; Nachon, F.; Chantegreil, F.; Soukup, O.; Prchal, L.; Malaguti, M.; et al. Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer’s Disease. J. Med. Chem. 2021, 64, 4972–4990. [Google Scholar] [CrossRef]
- Pasieka, A.; Panek, D.; Jończyk, J.; Godyń, J.; Szałaj, N.; Latacz, G.; Tabor, J.; Mezeiova, E.; Chantegreil, F.; Dias, J.; et al. Discovery of multifunctional anti-Alzheimer’s agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters. Eur. J. Med. Chem. 2021, 218, 113397. [Google Scholar] [CrossRef]
- Maček Hrvat, N.; Kalisiak, J.; Šinko, G.; Radić, Z.; Sharpless, K.B.; Taylor, P.; Kovarik, Z. Evaluation of high-affinity phenyltetrahydroisoquinoline aldoximes, linked through anti-triazoles, as reactivators of phosphylated cholinesterases. Toxicol. Lett. 2020, 321, 83–89. [Google Scholar] [CrossRef]
- Zandona, A.; Katalinić, M.; Šinko, G.; Radman Kastelic, A.; Primožič, I.; Kovarik, Z. Targeting organophosphorus compounds poisoning by novel quinuclidine-3 oximes: Development of butyrylcholinesterase-based bioscavengers. Arch. Toxicol. 2020, 94, 3157–3171. [Google Scholar] [CrossRef]
- Maraković, N.; Knežević, A.; Rončević, I.; Brazzolotto, X.; Kovarik, Z.; Šinko, G. Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases. Biochem. J. 2020, 477, 2771–2790. [Google Scholar] [CrossRef]
- Pajk, S.; Knez, D.; Košak, U.; Zorović, M.; Brazzolotto, X.; Coquelle, N.; Nachon, F.; Colletier, J.-P.; Živin, M.; Stojan, J.; et al. Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes. J. Enzym. Inhib. Med. Chem. 2020, 35, 498–505. [Google Scholar] [CrossRef]
- Bosak, A.; Opsenica, D.M.; Šinko, G.; Zlatar, M.; Kovarik, Z. Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase. Chem. Biol. Interact. 2019, 308, 101–109. [Google Scholar] [CrossRef]
- Meden, A.; Knez, D.; Jukič, M.; Brazzolotto, X.; Gršič, M.; Pišlar, A.; Zahirović, A.; Kos, J.; Nachon, F.; Svete, J.; et al. Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer’s disease. Chem. Commun. 2019, 55, 3765–3768. [Google Scholar] [CrossRef]
- Chalupova, K.; Korabecny, J.; Bartolini, M.; Monti, B.; Lamba, D.; Caliandro, R.; Pesaresi, A.; Brazzolotto, X.; Gastellier, A.-J.; Nachon, F.; et al. Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer’s disease. Eur. J. Med. Chem. 2019, 168, 491–514. [Google Scholar] [CrossRef] [PubMed]
- Bosak, A.; Ramić, A.; Šmidlehner, T.; Hrenar, T.; Primožič, I.; Kovarik, Z. Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold. PLoS ONE 2018, 13, e0205193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zorbaz, T.; Braïki, A.; Maraković, N.; Renou, J.; de la Mora, E.; Maček Hrvat, N.; Katalinić, M.; Silman, I.; Sussman, J.L.; Mercey, G.; et al. Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration. Chem. -A Eur. J. 2018, 24, 9675–9691. [Google Scholar] [CrossRef] [PubMed]
- Košak, U.; Brus, B.; Knez, D.; Žakelj, S.; Trontelj, J.; Pišlar, A.; Šink, R.; Jukič, M.; Živin, M.; Podkowa, A.; et al. The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity. J. Med. Chem. 2018, 61, 119–139. [Google Scholar] [CrossRef] [PubMed]
- Knez, D.; Coquelle, N.; Pišlar, A.; Žakelj, S.; Jukič, M.; Sova, M.; Mravljak, J.; Nachon, F.; Brazzolotto, X.; Kos, J.; et al. Multi-target-directed ligands for treating Alzheimer’s disease: Butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities. Eur. J. Med. Chem. 2018, 156, 598–617. [Google Scholar] [CrossRef]
- Bosak, A.; Knežević, A.; Gazić Smilović, I.; Šinko, G.; Kovarik, Z. Resorcinol-, catechol- and saligenin-based bronchodilating β2-agonists as inhibitors of human cholinesterase activity. J. Enzym. Inhib. Med. Chem. 2017, 32, 789–797. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bušić, V.; Katalinić, M.; Šinko, G.; Kovarik, Z.; Gašo-Sokač, D. Pyridoxal oxime derivative potency to reactivate cholinesterases inhibited by organophosphorus compounds. Toxicol. Lett. 2016, 262, 114–122. [Google Scholar] [CrossRef]
- Dighe, S.N.; Deora, G.S.; De la Mora, E.; Nachon, F.; Chan, S.; Parat, M.-O.; Brazzolotto, X.; Ross, B.P. Discovery and Structure–Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening. J. Med. Chem. 2016, 59, 7683–7689. [Google Scholar] [CrossRef]
- Knez, D.; Brus, B.; Coquelle, N.; Sosič, I.; Šink, R.; Brazzolotto, X.; Mravljak, J.; Colletier, J.-P.; Gobec, S. Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents. Bioorg. Med. Chem. 2015, 23, 4442–4452. [Google Scholar] [CrossRef]
- Brus, B.; Košak, U.; Turk, S.; Pišlar, A.; Coquelle, N.; Kos, J.; Stojan, J.; Colletier, J.-P.; Gobec, S. Discovery, Biological Evaluation, and Crystal Structure of a Novel Nanomolar Selective Butyrylcholinesterase Inhibitor. J. Med. Chem. 2014, 57, 8167–8179. [Google Scholar] [CrossRef] [PubMed]
- Nachon, F.; Carletti, E.; Ronco, C.; Trovaslet, M.; Nicolet, Y.; Jean, L.; Renard, P.-Y. Crystal structures of human cholinesterases in complex with huprine W and tacrine: Elements of specificity for anti-Alzheimer’s drugs targeting acetyl- and butyryl-cholinesterase. Biochem. J. 2013, 453, 393–399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Macdonald, I.R.; Martin, E.; Rosenberry, T.L.; Darvesh, S. Probing the Peripheral Site of Human Butyrylcholinesterase. Biochemistry 2012, 51, 7046–7053. [Google Scholar] [CrossRef] [PubMed]
- Ronco, C.; Foucault, R.; Gillon, E.; Bohn, P.; Nachon, F.; Jean, L.; Renard, P.-Y. New Huprine Derivatives Functionalized at Position 9 as Highly Potent Acetylcholinesterase Inhibitors. ChemMedChem 2011, 6, 876–888. [Google Scholar] [CrossRef]
- Katalinić, M.; Rusak, G.; Domaćinović Barović, J.; Šinko, G.; Jelić, D.; Antolović, R.; Kovarik, Z. Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase. Eur. J. Med. Chem. 2010, 45, 186–192. [Google Scholar] [CrossRef]
- Kovarik, Z.; Katalinic, M.; Bosak, A.; Sinko, G. Cholinesterase Interactions with Oximes. Curr. Bioact. Compd. 2010, 6, 9–15. [Google Scholar] [CrossRef]
- Saxena, A.; Redman, A.M.G.; Jiang, X.; Lockridge, O.; Doctor, B.P. Differences in active-site gorge dimensions of cholinesterases revealed by binding of inhibitors to human butyrylcholinesterase. Chem. Biol. Interact. 1999, 119–120, 61–69. [Google Scholar] [CrossRef]
- Tetko, I.V.; Gasteiger, J.; Todeschini, R.; Mauri, A.; Livingstone, D.; Ertl, P.; Palyulin, V.A.; Radchenko, E.V.; Zefirov, N.S.; Makarenko, A.S.; et al. Virtual Computational Chemistry Laboratory–Design and Description. J. Comput. Aided Mol. Des. 2005, 19, 453–463. [Google Scholar] [CrossRef]
- Online SMILES Translator and Structure File Generator 2020. Available online: https://cactus.nci.nih.gov/translate/ (accessed on 15 February 2022).
- Kier, L.B.; Hall, L.H. Molecular Connectivity VII: Specific Treatment of Heteroatoms. J. Pharm. Sci. 1976, 65, 1806–1809. [Google Scholar] [CrossRef]
- Kier, L.; Hall, L.H. Molecular Connectivity in Chemistry and Drug Research, 1st ed.; Academic Press: New York, NY, USA, 1976. [Google Scholar]
- Kier, L.; Hall, L.H. Molecular Connectivity in Structure-Activity Analysis; Willey: New York, NY, USA, 1986. [Google Scholar]
- Randić, M. On history of the Randić index and emerging hostility toward chemical graph theory. MATCH Commun. Math Comput. Chem. 2008, 59, 5–124. [Google Scholar]
- Milicević, A.; Raos, N. Influence of Chelate Ring Interactions on Copper(II) Chelate Stability Studied by Connectivity Index Functions. J. Phys. Chem. A 2008, 112, 7745–7749. [Google Scholar] [CrossRef] [PubMed]
- Raos, N.; Branica, G.; Miličević, A. The Use of Graph-theoretical Models to Evaluate Two Electroanalytical Methods for Determination of Stability Constants. Croat. Chem. Acta 2008, 81, 511–517. [Google Scholar]
- Miličević, A.; Raos, N. Estimation of stability constants of copper(II) and nickel(II) chelates with dipeptides by using topological indices. Polyhedron 2008, 27, 887–892. [Google Scholar] [CrossRef]
- Krammer, A.; Kirchhoff, P.D.; Jiang, X.; Venkatachalam, C.M.; Waldman, M. LigScore: A novel scoring function for predicting binding affinities. J. Mol. Graph. Model 2005, 23, 395–407. [Google Scholar] [CrossRef]
- Jain, A.N. Scoring noncovalent protein-ligand interactions: A continuous differentiable function tuned to compute binding affinities. J. Comput. Aided Mol. Des. 1996, 10, 427–440. [Google Scholar] [CrossRef]
- Gehlhaar, D.K.; Verkhivker, G.M.; Rejto, P.A.; Sherman, C.J.; Fogel, D.R.; Fogel, L.J.; Freer, S.T. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: Conformationally flexible docking by evolutionary programming. Chem. Biol. 1995, 2, 317–324. [Google Scholar] [CrossRef] [Green Version]
- Muegge, I. PMF Scoring Revisited. J. Med. Chem. 2006, 49, 5895–5902. [Google Scholar] [CrossRef]
- Brooks, B.R.; Bruccoleri, R.E.; Olafson, B.D.; States, D.J.; Swaminathan, S.; Karplus, M. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comp. Chem. 1983, 4, 187–217. [Google Scholar] [CrossRef]
- Wu, G.; Robertson, D.H.; Brooks, C.L.; Vieth, M. Detailed analysis of grid-based molecular docking: A case study of CDOCKER?A CHARMm-based MD docking algorithm. J. Comput. Chem. 2003, 24, 1549–1562. [Google Scholar] [CrossRef]
- Momany, F.A.; Rone, R. Validation of the general purpose QUANTA®3.2/CHARMm® force field. J. Comput. Chem. 1992, 13, 888–900. [Google Scholar] [CrossRef]
- Šinko, G. Assessment of scoring functions and in silico parameters for AChE-ligand interactions as a tool for predicting inhibition potency. Chem. Biol. Interact. 2019, 308, 216–223. [Google Scholar] [CrossRef] [PubMed]
- Lučić, B.; Trinajstić, N. Multivariate Regression Outperforms Several Robust Architectures of Neural Networks in QSAR Modeling. J. Chem. Inf. Comput. Sci. 1999, 39, 121–132. [Google Scholar] [CrossRef]
Model No. | No. of Descriptors | Set of Descriptors | r | rcv | S.E. | S.E.cv | Molecular Descriptor |
---|---|---|---|---|---|---|---|
1 | 1 | 856 | 0.765 | 0.762 | 0.93 | 0.93 | R2v |
2 | 2 | 0.832 | 0.829 | 0.80 | 0.81 | H2v, nROH | |
3 | 3 | 0.846 | 0.842 | 0.77 | 0.78 | H2v, nROH, BLI | |
4 | 1 | 336 | 0.703 | 0.698 | 1.02 | 1.03 | 2χv |
5 | 1 | 0.698 | 0.692 | 1.03 | 1.04 | 3χv | |
6 | 2 | 0.787 | 0.782 | 0.89 | 0.90 | 2χv, nROH | |
7 | 2 | 0.786 | 0.781 | 0.89 | 0.90 | 3χv, nROH | |
8 | 3 | 0.827 | 0.821 | 0.81 | 0.82 | 3χv, O-060, AlogP | |
9 | 3 | 0.823 | 0.817 | 0.82 | 0.83 | ZM2V, MWC03, nROH | |
10 | 4 | 0.845 | 0.839 | 0.77 | 0.78 | χT, nROH, O-060, AlogP2 | |
11 | 5 | 0.859 | 0.853 | 0.74 | 0.75 | piPC07, nCs, nCbH, nROH, nArOR |
Scoring Functions | r | S.E. | S.E.cv |
---|---|---|---|
CDOCKER Energy | 0.123 | 1.27 | 1.39 |
CDOCKER Interaction Energy | 0.523 | 1.09 | 1.28 |
LigScore1 | 0.533 | 1.08 | 1.21 |
LigScore2 | 0.428 | 1.16 | 1.33 |
PLP1 | 0.619 | 1.01 | 1.09 |
PLP2 | 0.689 | 0.93 | 1.01 |
PMF | 0.193 | 1.25 | 1.42 |
PMF04 | 0.067 | 1.28 | 1.47 |
Jain | 0.600 | 1.03 | 1.14 |
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Miličević, A.; Šinko, G. Evaluation of the Key Structural Features of Various Butyrylcholinesterase Inhibitors Using Simple Molecular Descriptors. Molecules 2022, 27, 6894. https://doi.org/10.3390/molecules27206894
Miličević A, Šinko G. Evaluation of the Key Structural Features of Various Butyrylcholinesterase Inhibitors Using Simple Molecular Descriptors. Molecules. 2022; 27(20):6894. https://doi.org/10.3390/molecules27206894
Chicago/Turabian StyleMiličević, Ante, and Goran Šinko. 2022. "Evaluation of the Key Structural Features of Various Butyrylcholinesterase Inhibitors Using Simple Molecular Descriptors" Molecules 27, no. 20: 6894. https://doi.org/10.3390/molecules27206894