ELECTRONIC, STRUCTURAL AND PHARMACOCINETIC CHARACTERIZATION OF TRICYCLIC ALKALOID ALTERNAMIDE A: A SEMI-EMPIRICAL QUANTUM STUDY AND ADMET
DOI:
https://doi.org/10.29121/granthaalayah.v7.i10.2019.417Keywords:
Alkaloid, Chagas disease, Neglected disease, Quantum study, Semi-empirical, Trypanosoma cruziAbstract [English]
Chagas disease is one of the biggest socioeconomic problems in Latin America. Caused by the protozoan parasite Trypanosoma cruzi, affecting 7 million people, causing approximately 14,000 deaths per year. Alternamide, a tricyclic alkaloid present in Alternanthera littoralis, an herbaceous plant found on beaches of the Brazilian its extracts are used in traditional medicine for treatment of infectious and inflammatory diseases, which showed anti Trypanocida activity. In this context, in the present work we present the results of the electronic, structural and pharmacokinetic characterization study of the promising phytopharmaceutical Alternamide A. Using the semi-empirical quantum formalism it was possible to identify the most stable conformation, boundary orbitals, calculate to identify nucleophilic sites and reactivity descriptors. Through in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) simulations, including solubility, blood-brain barrier (BHE), plasma protein binding, CYP2D6 binding, gastrointestinal absorption and hepatotoxicity, it was observed that good oral bioavailability and high-water solubility high gastrointestinal absorption. The synthetic accessibility score was 2.75, which means that it would be easy to synthesize the molecule under study. Highlighting what this study represents is a key step for future molecular docking and drug design studies for the development of inhibitors of the evolutionary forms of the molecule T-crossed.
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References
Dias, L.C., Dessoy, M.A., Silva JJN, Thiemann OH, Oliva G, Andricopulo AD. Chemotherapy of Chagas’ disease: State of the art and perspectives for the development of new drugs. Quim Nova. 2009;
Bermudez, J., Davies, C., Simonazzi, A., Pablo Real, J., Palma, S., Current drug therapy and pharmaceutical challenges for Chagas disease. Acta Tropica. 2016. DOI: https://doi.org/10.1016/j.actatropica.2015.12.017
Coura, J.R. Ripanosomose, doença de. E N D E M I a S /a R T I G O S. 1999;
De Oliveira Filho, G..B, Cardoso, M.V., Espíndola, J.W..P, Oliveira e Silva, D.A, Ferreira, R.S., Coelho, P.L., et al. Structural design, synthesis and pharmacological evaluation of thiazoles against Trypanosoma cruzi. Eur J Med Chem. 2017; DOI: https://doi.org/10.1016/j.ejmech.2017.09.047
Repetto, E.C., Zachariah, R., Kumar, A., Angheben, A., Gobbi, F., Anselmi, M., et al. Neglect of a Neglected Disease in Italy: The Challenge of Access-to-Care for Chagas Disease in Bergamo Area. PLoS Negl Trop Dis. 2015; DOI: https://doi.org/10.1371/journal.pntd.0004103
Moncayo,A., Silveira, A.C. Current epidemiological trends of Chagas disease in Latin America and future challenges: Epidemiology, surveillance, and health policies. In: American Trypanosomiasis Chagas Disease: One Hundred Years of Research: Second Edition. 2017. DOI: https://doi.org/10.1016/B978-0-12-801029-7.00004-6
De Menezes, R.P.B., Sampaio, T.L., Lima, D.B., Sousa, P.L., De Azevedo, I.E.P., Magalhães, E.P., et al. Antiparasitic effect of (−)-α-bisabolol against Trypanosoma cruzi Y strain forms. Diagn Microbiol Infect Dis [Internet]. 2019:114860. Available from: https://doi.org/10.1016/j.diagmicrobio.2019.06.012 DOI: https://doi.org/10.1016/j.diagmicrobio.2019.06.012
Koolen, H.H.F., Pral, E.M.F., Alfieri, S.C., Marinho, J.V.N., Serain, A.F., Hernández-Tasco, A.J.,. Antiprotozoal and antioxidant alkaloids from Alternanthera littoralis. Phytochemistry. 2017; DOI: https://doi.org/10.1016/j.phytochem.2016.11.008
Lima, A.R., Silva, J., Bezerra, L.L., Marinho, M.M., Marinho, E.S. Molecular docking of potential curcuminoids inhibitors of the NS1 protein of dengue virus. Int J Sci Eng Res. 2017;8(4).
Carneiro, S.S., Lima, A.R., Marinho, M.M., Marinho, E.S. In silico Study Of The Therapeutic Agent In The Treatment Of Non-Hodgkin’ s Lymphomas, Peripheral T- Cell Belinostat , A Semi-Empirical Approach. Imp J Interdiscip Res. 2016;(8):1645–8.
Oliveira, V.M. De, Marinho, M.M., Marinho, E.S., Semi-Empirical Quantum Characterization of the Drug Selexipag: HOMO and LUMO and Reactivity Descriptors. Int J Recent Res Rev. 2019; XII (2):15–20.
Henrique, C., Roberto, A., Marinho, E.S., Campos, O.S., Nithael,. F, Lucio M, Characterization of the natural insecticide methylcytisine: An in silico study using classic force field. Int J Recent Res Rev. 2019; XII (2):15–20.
Cheng, F., Li, W., Zhou, Y., Shen, J., Wu, Z., Liu, G., et al. AdmetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model. 2012; DOI: https://doi.org/10.1021/ci300367a
Tareq-Hassan Khan, M. Predictions of the ADMET Properties of Candidate Drug Molecules Utilizing Different QSAR/QSPR Modelling Approaches. Curr Drug Metab. 2010; DOI: https://doi.org/10.2174/138920010791514306
Chinthala, Y., Thakur, S., Tirunagari, S., Chinde, S., Domatti, A.K., Arigari, N.K., et al. Synthesis, docking and ADMET studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity. Eur J Med Chem. 2015; DOI: https://doi.org/10.1016/j.ejmech.2015.02.027
Atkins,. P, De Paula, J. Atkins’ physical chemistry / Peter Atkins, Julio de Paula. Physical chemistry. 2010.
Lopes, D.,Oliveira, S. De, Marinho, M.M., Marinho, E. S., Butanamide. Characterization in Silic of Anti-Epiletic Drug ( 2S ) -2- [( 4R ) -2- O--propylpyrrolidin--yl,. 2018; XI(4):5–12.
Csizmadia, P. MarvinSketch and MarvinView: Molecule Applets for the World Wide Web. In 2019.
Thompson, M.A., ArgusLab 401. Planaria Software LLC, Seattle, WA. ArgusLab 4.0. 1. Seattle; 2010.
Thompson, J.D., Cramer, C.J., Truhlar, D.G. Parameterization of charge model 3 for AM1, PM3, BLYP, and B3LYP. J Comput Chem. 2003; DOI: https://doi.org/10.1002/jcc.10244
Hanwell, M.D., Curtis, D.E., Lonie, D.C., Vandermeerschd, T., Zurek, E., Hutchison, G.R. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J Cheminform. 2012; DOI: https://doi.org/10.1186/1758-2946-4-17
Reges, M., Marinho, M.M., Marinho, E.S. Semi-Empirical Study of the Drug Riociguat , an Important Drug for Oral Treatment against Chronic Thromboembolic Pulmonary Hypertension. Int J Sci Eng Sci. 2017;1(1):13–7.
Araujo, G.A, Silva, E.P., Sanabio, R.G., Pinheiro, J.A., Albuquerque, M.B., Castro, R.R., et al. Characterization in Silico of the Structural Parameters of the Antifungal Agent Ketoconazole. Biol Chem Res. 2016;
Paes, L., Santos, W.L., Marinho, M.M., Marinho, E.S. ESTUDO DFT DO ALCALOIDE DICENTRINA: GAP, HOMO, LUMO, MESP E MULLIKEN. JOIN. 2017;(1).
Prabavathi, N., Nilufer, A., Krishnakumar, V. Molecular structure, vibrational, UV, NMR, hyperpolarizability, NBO and HOMO-LUMO analysis of Pteridine2,4-dione. Spectrochim Acta - Part A Mol Biomol Spectrosc. 2012; DOI: https://doi.org/10.1016/j.saa.2012.09.003
Mulliken, R.S. Electronic population analysis on LCAO-MO molecular wave functions. I. J Chem Phys. 1955; DOI: https://doi.org/10.1063/1.1740588
Atkins, P.W, Overton, T., Rourke, J., Weller, M., Armstrong, F., Hagerman, M. Shriver & Atkins’ Inorganic Chemistry. Shriver and Atkin’s inorganic chemistry. 2010.
Gopakumar, T.G., Meiss, J., Pouladsaz, D., Hietschold, M. HOMO-LUMO gap shrinking reveals tip-induced polarization of molecules in ultrathin layers: Tip-sample distance-dependent scanning tunneling spectroscopy on d8 (Ni, Pd, and Pt) phthalocyanines. J Phys Chem C. 2008; DOI: https://doi.org/10.1021/jp0771567
Suresh, Kumar. S., Athimoolam, S., Sridhar, B. XRD, vibrational spectra and quantum chemical studies of an anticancer drug: 6-Mercaptopurine. Spectrochim Acta - Part A Mol Biomol Spectrosc. 2015; DOI: https://doi.org/10.1016/j.saa.2015.02.104
Koopmans, T. Über die Zuordnung von Wellenfunktionen und Eigenwerten zu den Einzelnen Elektronen Eines Atoms. Physica. 1934; DOI: https://doi.org/10.1016/S0031-8914(34)90011-2
Vijayaraj, R., Subramanian, V., Chattaraj. P.K. Comparison of global reactivity descriptors calculated using various density functionals: A QSAR perspective. J Chem Theory Comput. 2009; DOI: https://doi.org/10.1021/ct900347f
Chermette, H. Chemical reactivity indexes in density functional theory. J Comput Chem. 1999; DOI: https://doi.org/10.1002/(SICI)1096-987X(19990115)20:1<129::AID-JCC13>3.0.CO;2-A
Padmanabhan, J., Parthasarathi, R., Subramanian, V., Chattaraj, P.K. Electrophilicity-based charge transfer descriptor. J Phys Chem A. 2007; DOI: https://doi.org/10.1021/jp0649549
Chattaraj, P.K., Sarkar, U. Theoretical Aspects of Chemical Reactivity. Theoretical and Computational Chemistry. 2007.
Parr, R.G., Pearson RG. Absolute hardness: companion parameter to absolute electronegativity. J Am Chem Soc [Internet]. 1983 Dec;105(26):7512–6. Available from: http://pubs.acs.org/doi/abs/10.1021/ja00364a005 DOI: https://doi.org/10.1021/ja00364a005
Parr, R.G., Chattaraj, P.K. Principle of Maximum Hardness. J Am Chem Soc. 1991; DOI: https://doi.org/10.1021/ja00005a072
Lee, C., Yang, W., Parr, R.G. Into a Functional of the Electron Density F F. Phys Rev B. 1988;
Okoli, P.T, Nzute, V.C, Durojaye, O.A., Chielo, O.H., Ajibo, Q.C., Udo, S.I., et al. An In-silico Pharmacokinetics Study on Cis- A Nutraceutical Compound with Anticancer Properties. 2019;7(3):1–7.
Silva, A.B.F, Marinho M.M., Mendes F.R.D.S. In Silico Study of Phytochemical Chlorogenic Acid: A Semi- Empirical Quantum Study and Adme. Int J Recent Res Rev. 2019; XII (2):34–9.
Daina, A., Michielin, O., Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; DOI: https://doi.org/10.1038/srep42717
Wildman, S.A, Crippen, G.M. Prediction of physicochemical parameters by atomic contributions. J Chem Inf Comput Sci. 1999; DOI: https://doi.org/10.1021/ci990307l
Lipinski, C.A, Lombardo, .F, Dominy, B.W., Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 2012. DOI: https://doi.org/10.1016/j.addr.2012.09.019
Waring, M.J. Defining optimum lipophilicity and molecular weight ranges for drug candidates-Molecular weight dependent lower log D limits based on permeability. Bioorganic Med Chem Lett. 2009; DOI: https://doi.org/10.1016/j.bmcl.2009.03.109
Lewars, E.G. Computational chemistry: Introduction to the theory and applications of molecular and quantum mechanics: Third Edition 2016. Computational Chemistry: Introduction to the Theory and Applications of Molecular and Quantum Mechanics: Third Edition 2016. 2016.
Marinho, E.S. Utilização Do Método Semi-Empírico Pm7 Para Caracterização Do Fármaco Atalureno : Homo ,. Rev Expressão Católica. 2016;1(1):177–84. DOI: https://doi.org/10.25191/recs.v1i1.1393
Atkins, P., Paula, J. de, Friedman, R.. Quanta, Matter, and Change: A molecular approach to physical chemistry. New York. 2009;
Atkins, P., Friedman, R., Molecular Quantum Mechanics Fourth Edition. Oxford Univ Press New York. 2005;
Eryilmaz, S., Gül, M., Inkaya, E., Taş, M. Isoxazole derivatives of alpha-pinene isomers: Synthesis, crystal structure, spectroscopic characterization (FT-IR/NMR/GC-MS) and DFT studies. J Mol Struct. 2016; DOI: https://doi.org/10.1016/j.molstruc.2015.11.079
Morgon, N.H., Custodio, R., Custódio, R., Morgan, N. H. and Custódio, R. Teoria do Funcional da Densidade. Quim Nov [Internet]. 1995;18(1):44. Available from: http://quimicanova.sbq.org.br/qn/qnol/1995/vol18n1/v18_n1_10.pdf
Reges, M., Marinho, M.M., Marinho, E.S. Structural Characterization of the Hypoglycemic Drug Glimepiride. Int J Recent Res Rev. 2018; XI (2):26–35.
Carneiro, S.S., Marinho, M.M., Marinho, E.S. Electronic / Structural Characterization of Antiparkinsonian Drug Istradefylline : A Semi-Empirical Study. Int J Recent Res Rev. 2017; X (4):9–14.
Marinho ES. A DFT study of synthetic drug topiroxostat: MEP, HOMO, LUMO. Int J Sci Eng Res. 2016;7(July):1264–70.
Eyre, R.J., Goss, J..P, MacLeod, R.M., Briddon, P.R. Stability of singly hydrated silanone on silicon quantum dot surfaces: Density functional simulations. Phys Chem Chem Phys. 2008; DOI: https://doi.org/10.1002/chin.200842001
Mohan, N., Suresh, C.H. A molecular electrostatic potential analysis of hydrogen, halogen, and dihydrogen bonds. J Phys Chem A. 2014; DOI: https://doi.org/10.1021/jp4115699
Lai, T.Y, Guo, J.D., Fettinger, J.C., Nagase, S., Power, P.P. Facile insertion of ethylene into a group 14 element-carbon bond: effects of the HOMO-LUMO energy gap on reactivity. Chem Commun. 2019; DOI: https://doi.org/10.1039/C8CC08488B
Rottschäfer, D., Sharma, M.K., Neumann, B., Stammler, H.G., Andrada, D.M., Ghadwal, R,S. A Modular Access to Divinyldiphosphenes with a Strikingly Small HOMO–LUMO Energy Gap. Chem - A Eur J. 2019; DOI: https://doi.org/10.1002/chem.201901204
AlAbbad, S., Sardot, T., Lekashvili, O., Decato, D., Lelj F., Ross J.B.A., et al. Trans influence and substituent effects on the HOMO-LUMO energy gap and Stokes shift in Ru mono-diimine derivatives. J Mol Struct. 2019; DOI: https://doi.org/10.1016/j.molstruc.2019.06.005
The Theoretical Prediction of Thermophysical properties, HOMO, LUMO, QSAR and Biological Indics of Cannabinoids (CBD) and Tetrahhdrocannabinol (THC) by Computational Chemistry. Adv J Chem A. 2019;
Arroio, A., Honório, K.M., Da Silva, A.B.F. Propriedades químico-quânticas empregadas em estudos das relações estrutura-atividade. Quimica Nova. 2010. DOI: https://doi.org/10.1590/S0100-40422010000300037
Rajan, V.K., Muraleedharan, K. A computational investigation on the structure, global parameters and antioxidant capacity of a polyphenol, Gallic acid. Food Chem [Internet]. 2017;220:93–9. Available from: http://dx.doi.org/10.1016/j.foodchem.2016.09.178 DOI: https://doi.org/10.1016/j.foodchem.2016.09.178
Ferreira, L.L.G, Andricopulo, A.D. ADMET modeling approaches in drug discovery. Drug Discovery Today. 2019. DOI: https://doi.org/10.1016/j.drudis.2019.03.015
Vora, J., Patel, S., Sinha, S., Sharma, S., Srivastava, A., Chhabria, M., et al. Molecular docking, QSAR and ADMET based mining of natural compounds against prime targets of HIV. J Biomol Struct Dyn. 2019; DOI: https://doi.org/10.1080/07391102.2017.1420489
Zapadka, M., Kaczmarek, M., Kupcewicz, B., Dekowski, P., Walkowiak, A., Kokotkiewicz, A., et al. An application of QSRR approach and multiple linear regression method for lipophilicity assessment of flavonoids. J Pharm Biomed Anal. 2019; DOI: https://doi.org/10.1016/j.jpba.2018.11.024
Daina, A., Zoete, V. A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem. 2016; DOI: https://doi.org/10.1002/cmdc.201600182
Singh, G., Satija, P., Singh, B., Sinha, S., Sehgal, R., Sahoo, S.C. Design, crystal structures and sustainable synthesis of family of antipyrine derivatives: Abolish to bacterial and parasitic infection. J Mol Struct. 2020; DOI: https://doi.org/10.1016/j.molstruc.2019.127010
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