Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos
ilustraciones, diagramas
- Autores:
-
Arias Quiroz, Estefany
- Tipo de recurso:
- Fecha de publicación:
- 2023
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/84510
- Palabra clave:
- 610 - Medicina y salud::615 - Farmacología y terapéutica
540 - Química y ciencias afines::547 - Química orgánica
Composición de medicamentos
Drug Compounding
Medicamentos
Drugs
GABAA
Tiazepínicos
Tiazolidínicos
Isoquinolínicos
Acoplamiento molecular
Ansiedad
Depresion
Antidepresivo
Ansiolitico
Molecular Docking
Thiazepins
Thiazolidins
Isoquinolines
Anxiety
Depression
Antidepressant
Anxiolytic
- Rights
- openAccess
- License
- Atribución-NoComercial-SinDerivadas 4.0 Internacional
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| dc.title.none.fl_str_mv |
Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos |
| dc.title.translated.none.fl_str_mv |
Virtual screening and evaluation of the tranquilizing activity of new thiazepine, thiazolidine and isoquinoline compounds |
| title |
Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos |
| spellingShingle |
Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos 610 - Medicina y salud::615 - Farmacología y terapéutica 540 - Química y ciencias afines::547 - Química orgánica Composición de medicamentos Drug Compounding Medicamentos Drugs GABAA Tiazepínicos Tiazolidínicos Isoquinolínicos Acoplamiento molecular Ansiedad Depresion Antidepresivo Ansiolitico Molecular Docking Thiazepins Thiazolidins Isoquinolines Anxiety Depression Antidepressant Anxiolytic |
| title_short |
Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos |
| title_full |
Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos |
| title_fullStr |
Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos |
| title_full_unstemmed |
Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos |
| title_sort |
Cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicos |
| dc.creator.fl_str_mv |
Arias Quiroz, Estefany |
| dc.contributor.advisor.none.fl_str_mv |
Cuervo Prado, Paola Andrea Guerrero Pabon, Mario Francisco |
| dc.contributor.author.none.fl_str_mv |
Arias Quiroz, Estefany |
| dc.contributor.researchgroup.spa.fl_str_mv |
Grupo de Estudios en Síntesis y Aplicaciones de Compuestos Heterocíclicos (Gesach) Grupo de Investigaciones en Farmacología Molecular (Farmol) |
| dc.subject.ddc.spa.fl_str_mv |
610 - Medicina y salud::615 - Farmacología y terapéutica 540 - Química y ciencias afines::547 - Química orgánica |
| topic |
610 - Medicina y salud::615 - Farmacología y terapéutica 540 - Química y ciencias afines::547 - Química orgánica Composición de medicamentos Drug Compounding Medicamentos Drugs GABAA Tiazepínicos Tiazolidínicos Isoquinolínicos Acoplamiento molecular Ansiedad Depresion Antidepresivo Ansiolitico Molecular Docking Thiazepins Thiazolidins Isoquinolines Anxiety Depression Antidepressant Anxiolytic |
| dc.subject.decs.spa.fl_str_mv |
Composición de medicamentos |
| dc.subject.decs.eng.fl_str_mv |
Drug Compounding |
| dc.subject.lemb.spa.fl_str_mv |
Medicamentos |
| dc.subject.lemb.eng.fl_str_mv |
Drugs |
| dc.subject.proposal.spa.fl_str_mv |
GABAA Tiazepínicos Tiazolidínicos Isoquinolínicos Acoplamiento molecular Ansiedad Depresion Antidepresivo Ansiolitico |
| dc.subject.proposal.eng.fl_str_mv |
Molecular Docking Thiazepins Thiazolidins Isoquinolines Anxiety Depression Antidepressant Anxiolytic |
| description |
ilustraciones, diagramas |
| publishDate |
2023 |
| dc.date.accessioned.none.fl_str_mv |
2023-08-09T19:30:57Z |
| dc.date.available.none.fl_str_mv |
2023-08-09T19:30:57Z |
| dc.date.issued.none.fl_str_mv |
2023 |
| dc.type.spa.fl_str_mv |
Trabajo de grado - Maestría |
| dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| dc.type.version.spa.fl_str_mv |
info:eu-repo/semantics/acceptedVersion |
| dc.type.content.spa.fl_str_mv |
Text |
| dc.type.redcol.spa.fl_str_mv |
http://purl.org/redcol/resource_type/TM |
| status_str |
acceptedVersion |
| dc.identifier.uri.none.fl_str_mv |
https://repositorio.unal.edu.co/handle/unal/84510 |
| dc.identifier.instname.spa.fl_str_mv |
Universidad Nacional de Colombia |
| dc.identifier.reponame.spa.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
| dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.unal.edu.co/ |
| url |
https://repositorio.unal.edu.co/handle/unal/84510 https://repositorio.unal.edu.co/ |
| identifier_str_mv |
Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia |
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spa |
| language |
spa |
| dc.relation.references.spa.fl_str_mv |
Adamson, R. H. (2016). The acute lethal dose 50 ( LD 50 ) of caffeine in albino rats. Regulatory Toxicology and Pharmacology, 80, 274–276. https://doi.org/10.1016/j.yrtph.2016.07.011 Allen, W. J., Balius, T. E., Mukherjee, S., Brozell, S. R., Moustakas, D. T., Lang, P. T., Case, D. A., Kuntz, I. D., & Rizzo, R. C. (2015). DOCK 6: Impact of new features and current docking performance. Journal of Computational Chemistry, 36(15), 1132–1156. https://doi.org/10.1002/jcc.23905 Armstrong, S. G., & Springs, O. F. B. (1887). United States Patent O-Ffice ~. 806, 5–7. https://patentimages.storage.googleapis.com/3b/f8/97/9257e4510e24fa/US2444536.pdf Babaev, O., Piletti Chatain, C., & Krueger-Burg, D. (2018). Inhibition in the amygdala anxiety circuitry. Experimental and Molecular Medicine, 50(4). https://doi.org/10.1038/s12276-018-0063-8 Ballón Paucara, W. G., & Grados Torrez, R. E. (2019). Acomplamiento molecular: criterios prácticos para la selección de ligandos biológicamente activos e identificación de nuevos blancos terapéuticos. Revista CON-CIENCIA, 7(2), 55–72. http://www.scielo.org.bo/scielo.php?script=sci_arttext&pid=S2310-02652019000200006&lng=es&nrm=iso&tlng=es Bansal, Y., & Silakari, O. (2014). European Journal of Medicinal Chemistry Multifunctional compounds : Smart molecules for multifactorial diseases. European Journal of Medicinal Chemistry, 76, 31–42. https://doi.org/10.1016/j.ejmech.2014.01.060 Barker-Haliski, M., & Steve White, H. (2020). Validated animal models for antiseizure drug (ASD) discovery: Advantages and potential pitfalls in ASD screening. Neuropharmacology, 167(August 2019), 107750. https://doi.org/10.1016/j.neuropharm.2019.107750 Becerra-Rivas, C., Cuervo-Prado, P., & Orozco-Lopez, F. (2019). Efficient catalyst-free tricomponent synthesis of new spiro[cyclohexane-1,4′-pyrazolo[3,4-e][1, 4]thiazepin]-7′(6′H)-ones. Synthetic Communications, 49(3), 367–376. https://doi.org/10.1080/00397911.2018.1554143 Bermejo, P. E., Dorado, R., Zea-Sevilla, M. A., & Sánchez Menéndez, V. (2011). Neuroanatomía de las decisiones financieras. Neurologia, 26(3), 173–181. https://doi.org/10.1016/j.nrl.2010.09.015 Birhan, Y. S., Bekhit, A. A., & Hymete, A. (2015). In vivo antimalarial evaluation of some derivatives. BMC Research Notes, 4–9. https://doi.org/10.1186/s13104-015-1578-x Bitencourt-Ferreira, G. O. V. F. W. (2019). Docking with AutoDock4. Methods in Molecular Biology, 2053(Figure 1), 44–45. Bogdanovaa, O., Kanekara, S., D’Ancid, K. E., & Renshawa, P. F. (2013). Factors influencing behavior in the forced swim test. Physiology & Behavior, 176(5), 139–148. https://doi.org/10.1016/j.physbeh.2013.05.012.Factors Bongarzone, S., & Bolognesi, M. L. (2011). The concept of privileged structures in rational drug design : focus on acridine and quinoline scaffolds in neurodegenerative and protozoan diseases. 251–268. Bormann, J. (2000). The ‘ ABC ’ of GABA receptors. 21(January), 151–153. Bouarab, C., Thompson, B., & Polter, A. M. (2019). VTA GABA Neurons at the Interface of Stress and Reward. Frontiers in Neural Circuits, 13(December), 1–12. https://doi.org/10.3389/fncir.2019.00078 Bouayyadi, A. (2020). Molecular docking analysis of α2-containing GABAA receptors with benzimidazoles derivatives. Bioinformation, 16(8), 611–619. https://doi.org/10.6026/97320630016611 Brozell, S. R., Mukherjee, S., Balius, T. E., Roe, D. R., Case, D. A., & Rizzo, R. C. (2012). Evaluation of DOCK 6 as a pose generation and database enrichment tool. Journal of Computer-Aided Molecular Design, 26(6), 749–773. https://doi.org/10.1007/s10822-012-9565-y Brylinski, M. (2018). Aromatic interactions at the ligand-protein interface: Implications for the development of docking scoring functions Michal. Chemical Biology & Drug Design, 176(5), 139–148. https://doi.org/10.1111/cbdd.13084.Aromatic Can, A., Dao, D. T., Terrillion, C. E., Piantadosi, S. C., Bhat, S., & Gould, T. D. (2012). The tail suspension test. Journal of Visualized Experiments, 58, 3–7. https://doi.org/10.3791/3769 Caron, G., Digiesi, V., Solaro, S., & Ermondi, G. (2020). Flexibility in early drug discovery: focus on the beyond-Rule-of-5 chemical space. Drug Discovery Today, 25(4), 621–627. https://doi.org/10.1016/j.drudis.2020.01.012 Castel-Branco, M. M., Alves, G. L., Figueiredo, I. V., Falcão, A. C., & Caramona, M. M. (2009). The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drugs. Methods and Findings in Experimental and Clinical Pharmacology, 31(2), 101–106. https://doi.org/10.1358/mf.2009.31.2.1338414 Chen, H., & Shi, D. (2011). Efficient one-pot synthesis of spiro[indoline-3,4′-pyrazolo[3,4-e][1, 4]thiazepine]dione via three-component reaction. Tetrahedron, 67(31), 5686–5692. https://doi.org/10.1016/j.tet.2011.05.069 Cheng, F., Shen, J., Yu, Y., Li, W., Liu, G., Lee, P. W., & Tang, Y. (2011). Chemosphere In silico prediction of Tetrahymena pyriformis toxicity for diverse industrial chemicals with substructure pattern recognition and machine learning methods. Chemosphere, 82(11), 1636–1643. https://doi.org/10.1016/j.chemosphere.2010.11.043 Cryan, J. F., Mombereau, C., & Vassout, A. (2005). The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neuroscience and Biobehavioral Reviews, 29(4–5), 571–625. https://doi.org/10.1016/j.neubiorev.2005.03.009 Danel, A., Gondek, E., Kucharek, M., Gut, A., Danel, A., Gondek, E., Kucharek, M., & Gut, A. (2022). 1H-Pyrazolo[3,4-b]quinolines: Synthesis and Properties over 100 Years of Research. Molecules. https://doi.org/10.3390/molecules27092775 Deng, X. Q., Song, M. X., Wang, S. Ben, & Quan, Z. S. (2014). Synthesis and evaluation of the anticonvulsant activity of 8-alkoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d][1,4]thiazepine derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry, 29(2), 272–280. https://doi.org/10.3109/14756366.2013.776555 Ding, K., Han, Z., & Wang, Z. (2009). Spiro Skeletons : A Class of Privileged Structure for Chiral Ligand Design. 32–41. https://doi.org/10.1002/asia.200800192 Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. Journal of Chemical Information and Modeling, 61(8), 3891–3898. https://doi.org/10.1021/acs.jcim.1c00203 Falco-Walter, J. (2020). Epilepsy-Definition, Classification, Pathophysiology, and Epidemiology. Seminars in Neurology, 40(6), 617–623. https://doi.org/10.1055/s-0040-1718719 Fan, J., & De Lannoy, I. A. M. (2014). Pharmacokinetics. Biochemical Pharmacology, 87(1), 93–120. https://doi.org/10.1016/j.bcp.2013.09.00 Fox, M. E. (2019). The molecular and cellular mechanisms of depression: a focus on reward circuitry. Mol Psychiatry, 176(1), 100–106. https://doi.org/10.1038/s41380-019-0415-3. Fradley, R. L., Guscott, M. R., Bull, S., Hallett, D. J., Goodacre, S. C., Wafford, K. A., Garrett, E. M., Newman, R. J., O’Meara, G. F., Whiting, P. J., Rosahl, T. W., Dawson, G. R., Reynolds, D. S., & Atack, J. R. (2007). Differential contribution of GABAA receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands. Journal of Psychopharmacology, 21(4), 384–391. https://doi.org/10.1177/0269881106067255 Gallina, A. M., Bork, P., & Bordo, D. (2014). Structural analysis of protein-ligand interactions: The binding of endogenous compounds and of synthetic drugs. Journal of Molecular Recognition, 27(2), 65–72. https://doi.org/10.1002/jmr.2332 Gao, G., Liang, N., Geng, H., Jiang, W., Fu, H., Feng, J., Hou, J., Feng, X., & Wang, Z. (2017). Spiro-Fused Perylene Diimide Arrays. 15914–15920. https://doi.org/10.1021/jacs.7b09140 Ghit, A., Assal, D., Al-shami, A. S., & Hussein, D. E. E. (2021). GABA A receptors : structure , function , pharmacology , and related disorders. 0. Golani, L. K., Platt, D. M., Rüedi-Bettschen, D., Edwanker, C., Huang, S., Poe, M. M., Furtmüller, R., Sieghart, W., Cook, J. M., & Rowlett, J. K. (2021). 8-Substituted Triazolobenzodiazepines: In Vitro and In Vivo Pharmacology in Relation to Structural Docking at the α1 Subunit-Containing GABAA Receptor. Frontiers in Pharmacology, 12(April), 1–15. https://doi.org/10.3389/fphar.2021.625233 Guedes, I. A., Pereira, F. S. S., & Dardenne, L. E. (2018). Empirical Scoring Functions for Structure-Based Virtual Screening : Applications , Critical Aspects , and Challenges. 9(September), 1–18. https://doi.org/10.3389/fphar.2018.01089 Guo, L., Wei, C., Jia, J., Zhao, L., & Quan, Z. (2009). European Journal of Medicinal Chemistry anticonvulsant activity. European Journal of Medicinal Chemistry, 44(3), 954–958. https://doi.org/10.1016/j.ejmech.2008.07.010 Hanrahan, J. R., Chebib, M., & Johnston, G. A. R. (2015). Interactions of flavonoids with ionotropic GABA receptors. In Advances in Pharmacology (1st ed., Vol. 72). Elsevier Inc. https://doi.org/10.1016/bs.apha.2014.10.007 Holguin, J. (2019). DISEÑO, SÍNTESIS Y CARACTERIZACIÓN DE COMPUESTOS ESPIROTIAZAHETEROCÍCLICOS CON POTENCIAL ACTIVIDAD SOBRE SISTEMA NERVIOSO CENTRAL (SNC). Universidad Nacional de Colombia, 1–9. https://doi.org/.1037//0033-2909.I26.1.78 Jain, V. S., Vora, D. K., & Ramaa, C. S. (2013). Bioorganic & Medicinal Chemistry Thiazolidine-2 , 4-diones : Progress towards multifarious applications. BIOORGANIC & MEDICINAL CHEMISTRY. https://doi.org/10.1016/j.bmc.2013.01.029 Kim, J. J., Anant, G., Jinfeng, T., Yuxuan, Z., Rebecca J., H., Shaotong, Z., Colleen M., N., Richard M., W. J., Erik, L., & Ryan E., H. (2020). Shared structural mechanisms of general anesthetics and benzodiazepines. Journal of Adolescent Health, 65(4), 303–308. https://doi.org/10.1038/s41586-020-2654-5. Kim, J. J., & Hibbs, R. E. (2021). Direct Structural Insights into GABAA Receptor Pharmacology. Trends in Biochemical Sciences, 46(6), 502–517. https://doi.org/10.1016/j.tibs.2021.01.011 Komada, M., Takao, K., & Miyakawa, T. (2008). Elevated plus maze for mice. Journal of Visualized Experiments, 22, 1–4. https://doi.org/10.3791/1088 Kraeuter, A. K., Guest, P. C., & Sarnyai, Z. (2019). The Open Field Test for Measuring Locomotor Activity and Anxiety-Like Behavior. Methods in Molecular Biology, 1916, 99–103. https://doi.org/10.1007/978-1-4939-8994-2_9 La-Vu, M., Tobias, B. C., Schuette, P. J., & Adhikari, A. (2020). To Approach or Avoid: An Introductory Overview of the Study of Anxiety Using Rodent Assays. Frontiers in Behavioral Neuroscience, 14(August), 1–7. https://doi.org/10.3389/fnbeh.2020.00145 Lapa, A. J., Souccar, C., Lima, M. T., & Lima, T. C. M. (2002). Métodos farmacológicos para el estudio de actividad sobre el sistema nervioso central. Métodos de Evaluación de La Actividad Farmacológica de Plantas Medicinales. Florianópolis, Santa Catarina, 70–90. Li, J., Fu, A., & Zhang, L. (2019). An Overview of Scoring Functions Used for Protein–Ligand Interactions in Molecular Docking. Interdisciplinary Sciences: Computational Life Sciences, 11(2), 320–328. https://doi.org/10.1007/s12539-019-00327-w Li, Q., & Salim, S. (2017). Structure-based virtual screening. Methods in Molecular Biology, 1558, 20–46. https://doi.org/10.2174/978160805142711101010020 Li, X., Du, Z., Wang, J., Wu, Z., Li, W., Liu, G., Shen, X., & Tang, Y. (2015). In Silico Estimation of Chemical Carcinogenicity with Binary and Ternary Classification Methods. 228–235. https://doi.org/10.1002/minf.201400127 Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2012). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings i. Advanced Drug Delivery Reviews, 64, 4–17. https://doi.org/10.1016/j.addr.2012.09.019 Maramai, S., Benchekroun, M., Ward, S. E., & Atack, J. R. (2020). Subtype Selective γ ‑ Aminobutyric Acid Type A Receptor ( GABA A R ) Modulators Acting at the Benzodiazepine Binding Site : An Update. https://doi.org/10.1021/acs.jmedchem.9b01312 Masiulis, S., Desai, R., Uchański, T., Martin, I. S., Karia, D., Malinauskas, T., Zivanov, J., & Pardon, E. (2019). GABA A receptor signalling mechanisms revealed by structural pharmacology. 565(7740), 454–459. https://doi.org/10.1038/s41586-018-0832-5.GABA Mathiasen, J. R., & Moser, V. C. (2018). The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents. Current Protocols in Pharmacology, 83(1), 1–18. https://doi.org/10.1002/cpph.43 Mishra, C. B., Kumari, S., & Tiwari, M. (2015). European Journal of Medicinal Chemistry Thiazole : A promising heterocycle for the development of potent CNS active agents. European Journal of Medicinal Chemistry, 92, 1–34. https://doi.org/10.1016/j.ejmech.2014.12.031 Moniruzzaman, M., Atikur Rahman, M., & Ferdous, A. (2015). Evaluation of sedative and hypnotic activity of ethanolic extract of Scoparia dulcis Linn. Evidence-Based Complementary and Alternative Medicine, 2015. https://doi.org/10.1155/2015/873954 Moore, G., Us, D. E., & Pierson, E. (2007). ( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2007 / 0010526 A1. 1(19). Moreira, de Brito, A. F., Fontana, C., de Carvalho, F. S., Sanz, G., Vaz, B. G., Lião, L. M., da Rocha, F. F., Verli, H., Menegatti, R., & Costa, E. A. (2020). Neuropharmacological assessment in mice and molecular docking of piperazine derivative LQFM212. Behavioural Brain Research, 394(June), 112827. https://doi.org/10.1016/j.bbr.2020.112827 Moreira, L. K. da S., de Brito, A. F., da Silva, D. M., Siqueira, L., da Silva, D. P. B., Cardoso, C. S., Florentino, I. F., de Carvalho, P. M. G., Ghedini, P. C., Menegatti, R., & Costa, E. A. (2021). Potential antidepressant-like effect of piperazine derivative LQFM212 in mice: Role of monoaminergic pathway and brain-derived neurotrophic factor. Behavioural Brain Research, 401(July 2020). https://doi.org/10.1016/j.bbr.2020.113066 Morris, G. M., Ruth, H., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). Software news and updates AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785–2791. https://doi.org/10.1002/jcc.21256 Mortelmans, K., & Zeiger, E. (2000). The Ames Salmonella/microsome mutagenicity assay. Mutation Research, 29–60. Muegge, I. (2016). Computer-aided drug design at Boehringer Ingelheim. Journal of Computer-Aided Molecular Design. https://doi.org/10.1007/s10822-016-9975-3 Nepali, K., Lee, H., & Liou, J. (2018). Nitro-Group-Containing Drugs. Journal of Medical Chemistry. https://doi.org/10.1021/acs.jmedchem.8b00147 Oda, A., Tsuchida, K., Takakura, T., Yamaotsu, N., & Hirono, S. (2006). Comparison of consensus scoring strategies for evaluating computational models of protein-ligand complexes. Journal of Chemical Information and Modeling, 46(1), 380–391. https://doi.org/10.1021/ci050283k Pardridge, W. M. (1995). Transport of small molecules through the blood-brain biology and methodology barrier : 310, 3–8. Pisula, W., Modlinska, K., Goncikowska, K., & Chrzanowska, A. (2021). Can the hole–board test predict a rat’s exploratory behavior in a free-exploration test? Animals, 11(4). https://doi.org/10.3390/ani11041068 Qu, N., He, Y., Wang, C., Xu, P., Yang, Y., Cai, X., Yu, K., Pei, Z., Hyseni, I., Sun, Z., Fukuda, M., Li, Y., Xu, Y., Plaza, B., Plaza, O. B., Mental, W., Sciences, H., Biology, C., & Plaza, O. B. (2020). A POMC-originated circuit regulates stress-induced hypophagia, depression and anhedonia. Mol Psychiatry, 25(5), 1006–1021. https://doi.org/10.1038/s41380-019-0506-1.A Redfern, W. S., Dymond, A., Strang, I., Storey, S., Grant, C., Marks, L., Barnard, C., Heys, C., Moyser, K., Greenwood, K., Cobey, D., Moore, N., Karp, N. A., & Prior, H. (2019). The functional observational battery and modified Irwin test as global neurobehavioral assessments in the rat: Pharmacological validation data and a comparison of methods. Journal of Pharmacological and Toxicological Methods, 98(May), 106591. Romanelli, M. N., & Gualtieri, F. (2007). The quest for the treatment of cognitive impairment : a 7 nicotinic and a 5 GABA A. 1365–1378. Sah, P. (2017). Fear, Anxiety, and the Amygdala. Neuron, 96(1), 1–2. https://doi.org/10.1016/j.neuron.2017.09.013 Saldívar-González, F., Prieto-Martínez, F. D., & Medina-Franco, J. L. (2017). Descubrimiento y desarrollo de fármacos: un enfoque computacional. Educacion Quimica, 28(1), 51–58. https://doi.org/10.1016/j.eq.2016.06.002 Santomauro, D. F., Mantilla Herrera, A. M., Shadid, J., Zheng, P., Ashbaugh, C., Pigott, D. M., Abbafati, C., Adolph, C., Amlag, J. O., Aravkin, A. Y., Bang-Jensen, B. L., Bertolacci, G. J., Bloom, S. S., Castellano, R., Castro, E., Chakrabarti, S., Chattopadhyay, J., Cogen, R. M., Collins, J. K., … Ferrari, A. J. (2021). Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. The Lancet, 398(10312), 1700–1712. https://doi.org/10.1016/S0140-6736(21)02143-7 Sargsyan, K., Grauffel, C., & Lim, C. (2017). How Molecular Size Impacts RMSD Applications in Molecular Dynamics Simulations. Journal of Chemical Theory and Computation, 13(4), 1518–1524. https://doi.org/10.1021/acs.jctc.7b00028 Shamma, M. (2012). The Isoquinoline Alkaloids: Chemistry and Pharmacology. In Elsevier. Shimada, T., & Yamagata, K. (2018). Pentylenetetrazole-induced kindling mouse model. Journal of Visualized Experiments, 2018(136), 1–10. https://doi.org/10.3791/56573 Sieghart, W. (2006). Structure , Pharmacology , and Function of GABA A Receptor Subtypes. 54(06). https://doi.org/10.1016/S1054-3589(06)54010-4 Sieghart, W. (2015). Allosteric Modulation of GABA A Receptors via Multiple Drug-Binding Sites. In Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part A (1st ed.). Elsevier Inc. https://doi.org/10.1016/bs.apha.2014.10.002 Solomon, V R, & Lee, H. (2011). Quinoline as a Privileged Scaffold in Cancer Drug Discovery. 1488–1508. Solomon, Viswas Raja, Tallapragada, V. J., Chebib, M., Johnston, G. A. R., & Hanrahan, J. R. (2019). GABA allosteric modulators: An overview of recent developments in non-benzodiazepine modulators. European Journal of Medicinal Chemistry, 171, 434–461. https://doi.org/10.1016/j.ejmech.2019.03.043 Tripathi, A. C., Ji, S., Naz, G., Kumar, P., & Verma, A. (2014). European Journal of Medicinal Chemistry 4-Thiazolidinones : The advances continue . 72, 52–77. https://doi.org/10.1016/j.ejmech.2013.11.017 Trott,O., Olson, A. J. (2019). Autodock vina: improving the speed and accuracy of docking. Journal of Computational Chemistry, 31(2), 455–461. https://doi.org/10.1002/jcc.21334.AutoDock Valencia, E. (2014). DISEÑO RACIONAL DE COMPUESTOS ESPIROTIAZOLIDÓNICOS, PIRAZOLOTIAZOLIDÓNICOS Y PIRAZOLO ß-LACTÁMICOS CON POTENCIAL ACTIVIDAD ANTIMICROBIANA. https://repositorio.unal.edu.co/handle/unal/54055 Veber, D. F., Johnson, S. R., Cheng, H., Smith, B. R., Ward, K. W., & Kopple, K. D. (2002). Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. 2615–2623. https://doi.org/10.1021/jm020017n Walters, W. P. (2012). Expert Opinion on Drug Discovery Going further than Lipinski ’ s rule in drug design Going further than Lipinski ’ s rule in drug design. 0441. https://doi.org/10.1517/17460441.2012.648612 Watanabe, M., Maernura, K., Kanbara, K., Tamayama, T., & Hayasaki, H. (2002). GABA and GABA Receptors in the Central Nervous System and Other Organs. 213. Zhu, H., Martin, T. M., Ye, L., Sedykh, A., Young, D. M., & Tropsha, A. (2009). Quantitative Structure - Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure. 1913–1921. |
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Universidad Nacional de Colombia |
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Bogotá - Ciencias - Maestría en Ciencias - Farmacología |
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Facultad de Ciencias |
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Bogotá, Colombia |
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Universidad Nacional de Colombia - Sede Bogotá |
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Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Cuervo Prado, Paola Andrea0ab24a7a447e04ec7a71d97faf26a7ecGuerrero Pabon, Mario Franciscodebd7ef8173a9e9f01b1d9ee0719c26aArias Quiroz, Estefanybb34e2c770eb277ab5ad3d98e366098cGrupo de Estudios en Síntesis y Aplicaciones de Compuestos Heterocíclicos (Gesach)Grupo de Investigaciones en Farmacología Molecular (Farmol)2023-08-09T19:30:57Z2023-08-09T19:30:57Z2023https://repositorio.unal.edu.co/handle/unal/84510Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramasLa química computacional permite el uso de múltiples herramientas para el desarrollo de nuevos fármacos. En este trabajo se exploró el enfoque de diseño de fármacos asociado a la estructura, usando el receptor GABA-A como diana para el estudio de acoplamiento molecular de tres series de compuestos orgánicos con los núcleos; espirotiazepinona, espirotiazolidona y tetrahidropirazoloquinolina. Para el docking molecular se empleó el sitio de unión de benzodiazepinas entre la interfaz α+/γ, perteneciente al receptor GABA-A. El estudio de acoplamiento fue llevado a cabo con los programas Autodock 4.2.6, AutoDock Vina y Dock6, posteriormente se realizó un consenso de puntuación con los puntajes de cada docking, lo cual permitió hacer una selección de los compuestos más promisorios, en conjunto con la predicción de las propiedades fisicoquímicas, farmacocinéticas y toxicológicas. Mediante el cribado virtual fueron seleccionados seis compuestos (dos por cada serie), dichas sustancias fueron evaluadas en un modelo murino a través de pruebas neurofarmacológicas comportamentales de tipo coordinación motora, ansiolítica, antidepresiva, anticonvulsivante y sedante-hipnótica. El cribado virtual reveló que los seis compuestos seleccionados presentaron interacciones de diferentes tipos con los aminoácidos Phe100D, Tyr58C, His102D, Tyr160D, Tyr210D, Ser205D, Phe77C, donde las interacciones más comunes fueron apilamiento pi-pi, pi-alquilo, pi en forma de T, pi-sulfuro y pi-sigma, las cuales presentaron correspondencia con aquellas interacciones entre el receptor y los fármacos de referencia. Adicionalmente se presentaron interacciones con halógeno cuando el compuesto de prueba contenía un sustituyente de este tipo en posición para del sistema bencenoide. Posteriormente, se realizaron pruebas comportamentales en ratones de laboratorio con los seis compuestos seleccionados; los resultados obtenidos no revelaron una actividad de tipo tranquilizante en las dosis evaluadas. Es necesario proseguir con bioensayos a dosis más altas y continuar con el estudio de la correspondencia de los resultados in silico e in vivo. (Texto tomado de la fuente)Computational chemistry allows the use of multiple tools for the development of new drugs. In this work, the structure-associated drug design approach was explored using the GABA-A receptor as a target for the molecular docking study of three series of organic compounds with the nuclei; spirothiazepinone, spirothiazolidone and tetrahydropyrazoloquinoline. For molecular docking, the benzodiazepine binding site between the α+/γ interface belonging to the GABA-A receptor was used. The docking study was carried out with the programs Autodock 4.2.6, AutoDock Vina and Dock6, subsequently a consensus scoring was performed with the scores of each docking, which allowed making a selection of the most promising compounds, in conjunction with the prediction of physicochemical, pharmacokinetic and toxicological properties. By means of virtual screening, six compounds were selected (two for each series), and these substances were evaluated in a murine model through behavioral neuropharmacological tests of motor coordination, anxiolytic, antidepressant, anticonvulsant and sedative-hypnotic type. Virtual screening revealed that the six selected compounds exhibited interactions of different types with the amino acids Phe100D, Tyr58C, His102D, Tyr160D, Tyr210D, Ser205D, Phe77C, where the most common interactions were pi-pi, pi-alkyl, T-shaped pi, pi-sulfide and pi-sigma stacking, which showed correspondence with those interactions between the receptor and the reference drugs. In addition, halogen interactions occurred when the test compound contained a halogen substituent in the para position of the benzenoid system. Subsequently, behavioral tests were performed on laboratory mice with the six selected compounds; the results obtained did not reveal a tranquilizer-type activity at the doses evaluated. It is necessary to continue with bioassays at higher doses and to continue with the study of the correspondence of the in silico and in vivo results.MINCIENCIASMaestríaMagíster en Ciencias - FarmacologíaFarmacologiaDiseño de fármacos asistido por computadora201 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Ciencias - FarmacologíaFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::615 - Farmacología y terapéutica540 - Química y ciencias afines::547 - Química orgánicaComposición de medicamentosDrug CompoundingMedicamentosDrugsGABAATiazepínicosTiazolidínicosIsoquinolínicosAcoplamiento molecularAnsiedadDepresionAntidepresivoAnsioliticoMolecular DockingThiazepinsThiazolidinsIsoquinolinesAnxietyDepressionAntidepressantAnxiolyticCribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos e isoquinolínicosVirtual screening and evaluation of the tranquilizing activity of new thiazepine, thiazolidine and isoquinoline compoundsTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMAdamson, R. H. (2016). The acute lethal dose 50 ( LD 50 ) of caffeine in albino rats. Regulatory Toxicology and Pharmacology, 80, 274–276. https://doi.org/10.1016/j.yrtph.2016.07.011Allen, W. J., Balius, T. E., Mukherjee, S., Brozell, S. R., Moustakas, D. T., Lang, P. T., Case, D. A., Kuntz, I. D., & Rizzo, R. C. (2015). DOCK 6: Impact of new features and current docking performance. Journal of Computational Chemistry, 36(15), 1132–1156. https://doi.org/10.1002/jcc.23905Armstrong, S. G., & Springs, O. F. B. (1887). United States Patent O-Ffice ~. 806, 5–7. https://patentimages.storage.googleapis.com/3b/f8/97/9257e4510e24fa/US2444536.pdfBabaev, O., Piletti Chatain, C., & Krueger-Burg, D. (2018). Inhibition in the amygdala anxiety circuitry. Experimental and Molecular Medicine, 50(4). https://doi.org/10.1038/s12276-018-0063-8Ballón Paucara, W. G., & Grados Torrez, R. E. (2019). Acomplamiento molecular: criterios prácticos para la selección de ligandos biológicamente activos e identificación de nuevos blancos terapéuticos. Revista CON-CIENCIA, 7(2), 55–72. http://www.scielo.org.bo/scielo.php?script=sci_arttext&pid=S2310-02652019000200006&lng=es&nrm=iso&tlng=esBansal, Y., & Silakari, O. (2014). European Journal of Medicinal Chemistry Multifunctional compounds : Smart molecules for multifactorial diseases. European Journal of Medicinal Chemistry, 76, 31–42. https://doi.org/10.1016/j.ejmech.2014.01.060Barker-Haliski, M., & Steve White, H. (2020). Validated animal models for antiseizure drug (ASD) discovery: Advantages and potential pitfalls in ASD screening. Neuropharmacology, 167(August 2019), 107750. https://doi.org/10.1016/j.neuropharm.2019.107750Becerra-Rivas, C., Cuervo-Prado, P., & Orozco-Lopez, F. (2019). Efficient catalyst-free tricomponent synthesis of new spiro[cyclohexane-1,4′-pyrazolo[3,4-e][1, 4]thiazepin]-7′(6′H)-ones. Synthetic Communications, 49(3), 367–376. https://doi.org/10.1080/00397911.2018.1554143Bermejo, P. E., Dorado, R., Zea-Sevilla, M. A., & Sánchez Menéndez, V. (2011). Neuroanatomía de las decisiones financieras. Neurologia, 26(3), 173–181. https://doi.org/10.1016/j.nrl.2010.09.015Birhan, Y. S., Bekhit, A. A., & Hymete, A. (2015). In vivo antimalarial evaluation of some derivatives. BMC Research Notes, 4–9. https://doi.org/10.1186/s13104-015-1578-xBitencourt-Ferreira, G. O. V. F. W. (2019). Docking with AutoDock4. Methods in Molecular Biology, 2053(Figure 1), 44–45.Bogdanovaa, O., Kanekara, S., D’Ancid, K. E., & Renshawa, P. F. (2013). Factors influencing behavior in the forced swim test. Physiology & Behavior, 176(5), 139–148. https://doi.org/10.1016/j.physbeh.2013.05.012.FactorsBongarzone, S., & Bolognesi, M. L. (2011). The concept of privileged structures in rational drug design : focus on acridine and quinoline scaffolds in neurodegenerative and protozoan diseases. 251–268.Bormann, J. (2000). The ‘ ABC ’ of GABA receptors. 21(January), 151–153.Bouarab, C., Thompson, B., & Polter, A. M. (2019). VTA GABA Neurons at the Interface of Stress and Reward. Frontiers in Neural Circuits, 13(December), 1–12. https://doi.org/10.3389/fncir.2019.00078Bouayyadi, A. (2020). Molecular docking analysis of α2-containing GABAA receptors with benzimidazoles derivatives. Bioinformation, 16(8), 611–619. https://doi.org/10.6026/97320630016611Brozell, S. R., Mukherjee, S., Balius, T. E., Roe, D. R., Case, D. A., & Rizzo, R. C. (2012). Evaluation of DOCK 6 as a pose generation and database enrichment tool. Journal of Computer-Aided Molecular Design, 26(6), 749–773. https://doi.org/10.1007/s10822-012-9565-yBrylinski, M. (2018). Aromatic interactions at the ligand-protein interface: Implications for the development of docking scoring functions Michal. Chemical Biology & Drug Design, 176(5), 139–148. https://doi.org/10.1111/cbdd.13084.AromaticCan, A., Dao, D. T., Terrillion, C. E., Piantadosi, S. C., Bhat, S., & Gould, T. D. (2012). The tail suspension test. Journal of Visualized Experiments, 58, 3–7. https://doi.org/10.3791/3769Caron, G., Digiesi, V., Solaro, S., & Ermondi, G. (2020). Flexibility in early drug discovery: focus on the beyond-Rule-of-5 chemical space. Drug Discovery Today, 25(4), 621–627. https://doi.org/10.1016/j.drudis.2020.01.012Castel-Branco, M. M., Alves, G. L., Figueiredo, I. V., Falcão, A. C., & Caramona, M. M. (2009). The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drugs. Methods and Findings in Experimental and Clinical Pharmacology, 31(2), 101–106. https://doi.org/10.1358/mf.2009.31.2.1338414Chen, H., & Shi, D. (2011). Efficient one-pot synthesis of spiro[indoline-3,4′-pyrazolo[3,4-e][1, 4]thiazepine]dione via three-component reaction. Tetrahedron, 67(31), 5686–5692. https://doi.org/10.1016/j.tet.2011.05.069Cheng, F., Shen, J., Yu, Y., Li, W., Liu, G., Lee, P. W., & Tang, Y. (2011). Chemosphere In silico prediction of Tetrahymena pyriformis toxicity for diverse industrial chemicals with substructure pattern recognition and machine learning methods. Chemosphere, 82(11), 1636–1643. https://doi.org/10.1016/j.chemosphere.2010.11.043Cryan, J. F., Mombereau, C., & Vassout, A. (2005). The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neuroscience and Biobehavioral Reviews, 29(4–5), 571–625. https://doi.org/10.1016/j.neubiorev.2005.03.009Danel, A., Gondek, E., Kucharek, M., Gut, A., Danel, A., Gondek, E., Kucharek, M., & Gut, A. (2022). 1H-Pyrazolo[3,4-b]quinolines: Synthesis and Properties over 100 Years of Research. Molecules. https://doi.org/10.3390/molecules27092775Deng, X. Q., Song, M. X., Wang, S. Ben, & Quan, Z. S. (2014). Synthesis and evaluation of the anticonvulsant activity of 8-alkoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d][1,4]thiazepine derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry, 29(2), 272–280. https://doi.org/10.3109/14756366.2013.776555Ding, K., Han, Z., & Wang, Z. (2009). Spiro Skeletons : A Class of Privileged Structure for Chiral Ligand Design. 32–41. https://doi.org/10.1002/asia.200800192Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. Journal of Chemical Information and Modeling, 61(8), 3891–3898. https://doi.org/10.1021/acs.jcim.1c00203Falco-Walter, J. (2020). Epilepsy-Definition, Classification, Pathophysiology, and Epidemiology. Seminars in Neurology, 40(6), 617–623. https://doi.org/10.1055/s-0040-1718719Fan, J., & De Lannoy, I. A. M. (2014). Pharmacokinetics. Biochemical Pharmacology, 87(1), 93–120. https://doi.org/10.1016/j.bcp.2013.09.00Fox, M. E. (2019). The molecular and cellular mechanisms of depression: a focus on reward circuitry. Mol Psychiatry, 176(1), 100–106. https://doi.org/10.1038/s41380-019-0415-3.Fradley, R. L., Guscott, M. R., Bull, S., Hallett, D. J., Goodacre, S. C., Wafford, K. A., Garrett, E. M., Newman, R. J., O’Meara, G. F., Whiting, P. J., Rosahl, T. W., Dawson, G. R., Reynolds, D. S., & Atack, J. R. (2007). Differential contribution of GABAA receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands. Journal of Psychopharmacology, 21(4), 384–391. https://doi.org/10.1177/0269881106067255Gallina, A. M., Bork, P., & Bordo, D. (2014). Structural analysis of protein-ligand interactions: The binding of endogenous compounds and of synthetic drugs. Journal of Molecular Recognition, 27(2), 65–72. https://doi.org/10.1002/jmr.2332Gao, G., Liang, N., Geng, H., Jiang, W., Fu, H., Feng, J., Hou, J., Feng, X., & Wang, Z. (2017). Spiro-Fused Perylene Diimide Arrays. 15914–15920. https://doi.org/10.1021/jacs.7b09140Ghit, A., Assal, D., Al-shami, A. S., & Hussein, D. E. E. (2021). GABA A receptors : structure , function , pharmacology , and related disorders. 0.Golani, L. K., Platt, D. M., Rüedi-Bettschen, D., Edwanker, C., Huang, S., Poe, M. M., Furtmüller, R., Sieghart, W., Cook, J. M., & Rowlett, J. K. (2021). 8-Substituted Triazolobenzodiazepines: In Vitro and In Vivo Pharmacology in Relation to Structural Docking at the α1 Subunit-Containing GABAA Receptor. Frontiers in Pharmacology, 12(April), 1–15. https://doi.org/10.3389/fphar.2021.625233Guedes, I. A., Pereira, F. S. S., & Dardenne, L. E. (2018). Empirical Scoring Functions for Structure-Based Virtual Screening : Applications , Critical Aspects , and Challenges. 9(September), 1–18. https://doi.org/10.3389/fphar.2018.01089Guo, L., Wei, C., Jia, J., Zhao, L., & Quan, Z. (2009). European Journal of Medicinal Chemistry anticonvulsant activity. European Journal of Medicinal Chemistry, 44(3), 954–958. https://doi.org/10.1016/j.ejmech.2008.07.010Hanrahan, J. R., Chebib, M., & Johnston, G. A. R. (2015). Interactions of flavonoids with ionotropic GABA receptors. In Advances in Pharmacology (1st ed., Vol. 72). Elsevier Inc. https://doi.org/10.1016/bs.apha.2014.10.007Holguin, J. (2019). DISEÑO, SÍNTESIS Y CARACTERIZACIÓN DE COMPUESTOS ESPIROTIAZAHETEROCÍCLICOS CON POTENCIAL ACTIVIDAD SOBRE SISTEMA NERVIOSO CENTRAL (SNC). Universidad Nacional de Colombia, 1–9. https://doi.org/.1037//0033-2909.I26.1.78Jain, V. S., Vora, D. K., & Ramaa, C. S. (2013). Bioorganic & Medicinal Chemistry Thiazolidine-2 , 4-diones : Progress towards multifarious applications. BIOORGANIC & MEDICINAL CHEMISTRY. https://doi.org/10.1016/j.bmc.2013.01.029Kim, J. J., Anant, G., Jinfeng, T., Yuxuan, Z., Rebecca J., H., Shaotong, Z., Colleen M., N., Richard M., W. J., Erik, L., & Ryan E., H. (2020). Shared structural mechanisms of general anesthetics and benzodiazepines. Journal of Adolescent Health, 65(4), 303–308. https://doi.org/10.1038/s41586-020-2654-5.Kim, J. J., & Hibbs, R. E. (2021). Direct Structural Insights into GABAA Receptor Pharmacology. Trends in Biochemical Sciences, 46(6), 502–517. https://doi.org/10.1016/j.tibs.2021.01.011Komada, M., Takao, K., & Miyakawa, T. (2008). Elevated plus maze for mice. Journal of Visualized Experiments, 22, 1–4. https://doi.org/10.3791/1088Kraeuter, A. K., Guest, P. C., & Sarnyai, Z. (2019). The Open Field Test for Measuring Locomotor Activity and Anxiety-Like Behavior. Methods in Molecular Biology, 1916, 99–103. https://doi.org/10.1007/978-1-4939-8994-2_9La-Vu, M., Tobias, B. C., Schuette, P. J., & Adhikari, A. (2020). To Approach or Avoid: An Introductory Overview of the Study of Anxiety Using Rodent Assays. Frontiers in Behavioral Neuroscience, 14(August), 1–7. https://doi.org/10.3389/fnbeh.2020.00145Lapa, A. J., Souccar, C., Lima, M. T., & Lima, T. C. M. (2002). Métodos farmacológicos para el estudio de actividad sobre el sistema nervioso central. Métodos de Evaluación de La Actividad Farmacológica de Plantas Medicinales. Florianópolis, Santa Catarina, 70–90.Li, J., Fu, A., & Zhang, L. (2019). An Overview of Scoring Functions Used for Protein–Ligand Interactions in Molecular Docking. Interdisciplinary Sciences: Computational Life Sciences, 11(2), 320–328. https://doi.org/10.1007/s12539-019-00327-wLi, Q., & Salim, S. (2017). Structure-based virtual screening. Methods in Molecular Biology, 1558, 20–46. https://doi.org/10.2174/978160805142711101010020Li, X., Du, Z., Wang, J., Wu, Z., Li, W., Liu, G., Shen, X., & Tang, Y. (2015). In Silico Estimation of Chemical Carcinogenicity with Binary and Ternary Classification Methods. 228–235. https://doi.org/10.1002/minf.201400127Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2012). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings i. Advanced Drug Delivery Reviews, 64, 4–17. https://doi.org/10.1016/j.addr.2012.09.019Maramai, S., Benchekroun, M., Ward, S. E., & Atack, J. R. (2020). Subtype Selective γ ‑ Aminobutyric Acid Type A Receptor ( GABA A R ) Modulators Acting at the Benzodiazepine Binding Site : An Update. https://doi.org/10.1021/acs.jmedchem.9b01312Masiulis, S., Desai, R., Uchański, T., Martin, I. S., Karia, D., Malinauskas, T., Zivanov, J., & Pardon, E. (2019). GABA A receptor signalling mechanisms revealed by structural pharmacology. 565(7740), 454–459. https://doi.org/10.1038/s41586-018-0832-5.GABAMathiasen, J. R., & Moser, V. C. (2018). The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents. Current Protocols in Pharmacology, 83(1), 1–18. https://doi.org/10.1002/cpph.43Mishra, C. B., Kumari, S., & Tiwari, M. (2015). European Journal of Medicinal Chemistry Thiazole : A promising heterocycle for the development of potent CNS active agents. European Journal of Medicinal Chemistry, 92, 1–34. https://doi.org/10.1016/j.ejmech.2014.12.031Moniruzzaman, M., Atikur Rahman, M., & Ferdous, A. (2015). Evaluation of sedative and hypnotic activity of ethanolic extract of Scoparia dulcis Linn. Evidence-Based Complementary and Alternative Medicine, 2015. https://doi.org/10.1155/2015/873954Moore, G., Us, D. E., & Pierson, E. (2007). ( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2007 / 0010526 A1. 1(19).Moreira, de Brito, A. F., Fontana, C., de Carvalho, F. S., Sanz, G., Vaz, B. G., Lião, L. M., da Rocha, F. F., Verli, H., Menegatti, R., & Costa, E. A. (2020). Neuropharmacological assessment in mice and molecular docking of piperazine derivative LQFM212. Behavioural Brain Research, 394(June), 112827. https://doi.org/10.1016/j.bbr.2020.112827Moreira, L. K. da S., de Brito, A. F., da Silva, D. M., Siqueira, L., da Silva, D. P. B., Cardoso, C. S., Florentino, I. F., de Carvalho, P. M. G., Ghedini, P. C., Menegatti, R., & Costa, E. A. (2021). Potential antidepressant-like effect of piperazine derivative LQFM212 in mice: Role of monoaminergic pathway and brain-derived neurotrophic factor. Behavioural Brain Research, 401(July 2020). https://doi.org/10.1016/j.bbr.2020.113066Morris, G. M., Ruth, H., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). Software news and updates AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785–2791. https://doi.org/10.1002/jcc.21256Mortelmans, K., & Zeiger, E. (2000). The Ames Salmonella/microsome mutagenicity assay. Mutation Research, 29–60.Muegge, I. (2016). Computer-aided drug design at Boehringer Ingelheim. Journal of Computer-Aided Molecular Design. https://doi.org/10.1007/s10822-016-9975-3Nepali, K., Lee, H., & Liou, J. (2018). Nitro-Group-Containing Drugs. Journal of Medical Chemistry. https://doi.org/10.1021/acs.jmedchem.8b00147Oda, A., Tsuchida, K., Takakura, T., Yamaotsu, N., & Hirono, S. (2006). Comparison of consensus scoring strategies for evaluating computational models of protein-ligand complexes. Journal of Chemical Information and Modeling, 46(1), 380–391. https://doi.org/10.1021/ci050283kPardridge, W. M. (1995). Transport of small molecules through the blood-brain biology and methodology barrier : 310, 3–8.Pisula, W., Modlinska, K., Goncikowska, K., & Chrzanowska, A. (2021). Can the hole–board test predict a rat’s exploratory behavior in a free-exploration test? Animals, 11(4). https://doi.org/10.3390/ani11041068Qu, N., He, Y., Wang, C., Xu, P., Yang, Y., Cai, X., Yu, K., Pei, Z., Hyseni, I., Sun, Z., Fukuda, M., Li, Y., Xu, Y., Plaza, B., Plaza, O. B., Mental, W., Sciences, H., Biology, C., & Plaza, O. B. (2020). A POMC-originated circuit regulates stress-induced hypophagia, depression and anhedonia. Mol Psychiatry, 25(5), 1006–1021. https://doi.org/10.1038/s41380-019-0506-1.ARedfern, W. S., Dymond, A., Strang, I., Storey, S., Grant, C., Marks, L., Barnard, C., Heys, C., Moyser, K., Greenwood, K., Cobey, D., Moore, N., Karp, N. A., & Prior, H. (2019). The functional observational battery and modified Irwin test as global neurobehavioral assessments in the rat: Pharmacological validation data and a comparison of methods. Journal of Pharmacological and Toxicological Methods, 98(May), 106591.Romanelli, M. N., & Gualtieri, F. (2007). The quest for the treatment of cognitive impairment : a 7 nicotinic and a 5 GABA A. 1365–1378.Sah, P. (2017). Fear, Anxiety, and the Amygdala. Neuron, 96(1), 1–2. https://doi.org/10.1016/j.neuron.2017.09.013Saldívar-González, F., Prieto-Martínez, F. D., & Medina-Franco, J. L. (2017). Descubrimiento y desarrollo de fármacos: un enfoque computacional. Educacion Quimica, 28(1), 51–58. https://doi.org/10.1016/j.eq.2016.06.002Santomauro, D. F., Mantilla Herrera, A. M., Shadid, J., Zheng, P., Ashbaugh, C., Pigott, D. M., Abbafati, C., Adolph, C., Amlag, J. O., Aravkin, A. Y., Bang-Jensen, B. L., Bertolacci, G. J., Bloom, S. S., Castellano, R., Castro, E., Chakrabarti, S., Chattopadhyay, J., Cogen, R. M., Collins, J. K., … Ferrari, A. J. (2021). Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. The Lancet, 398(10312), 1700–1712. https://doi.org/10.1016/S0140-6736(21)02143-7Sargsyan, K., Grauffel, C., & Lim, C. (2017). How Molecular Size Impacts RMSD Applications in Molecular Dynamics Simulations. Journal of Chemical Theory and Computation, 13(4), 1518–1524. https://doi.org/10.1021/acs.jctc.7b00028Shamma, M. (2012). The Isoquinoline Alkaloids: Chemistry and Pharmacology. In Elsevier.Shimada, T., & Yamagata, K. (2018). Pentylenetetrazole-induced kindling mouse model. Journal of Visualized Experiments, 2018(136), 1–10. https://doi.org/10.3791/56573Sieghart, W. (2006). Structure , Pharmacology , and Function of GABA A Receptor Subtypes. 54(06). https://doi.org/10.1016/S1054-3589(06)54010-4Sieghart, W. (2015). Allosteric Modulation of GABA A Receptors via Multiple Drug-Binding Sites. In Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part A (1st ed.). Elsevier Inc. https://doi.org/10.1016/bs.apha.2014.10.002Solomon, V R, & Lee, H. (2011). Quinoline as a Privileged Scaffold in Cancer Drug Discovery. 1488–1508.Solomon, Viswas Raja, Tallapragada, V. J., Chebib, M., Johnston, G. A. R., & Hanrahan, J. R. (2019). GABA allosteric modulators: An overview of recent developments in non-benzodiazepine modulators. European Journal of Medicinal Chemistry, 171, 434–461. https://doi.org/10.1016/j.ejmech.2019.03.043Tripathi, A. C., Ji, S., Naz, G., Kumar, P., & Verma, A. (2014). European Journal of Medicinal Chemistry 4-Thiazolidinones : The advances continue . 72, 52–77. https://doi.org/10.1016/j.ejmech.2013.11.017Trott,O., Olson, A. J. (2019). Autodock vina: improving the speed and accuracy of docking. Journal of Computational Chemistry, 31(2), 455–461. https://doi.org/10.1002/jcc.21334.AutoDockValencia, E. (2014). DISEÑO RACIONAL DE COMPUESTOS ESPIROTIAZOLIDÓNICOS, PIRAZOLOTIAZOLIDÓNICOS Y PIRAZOLO ß-LACTÁMICOS CON POTENCIAL ACTIVIDAD ANTIMICROBIANA. https://repositorio.unal.edu.co/handle/unal/54055Veber, D. F., Johnson, S. R., Cheng, H., Smith, B. R., Ward, K. W., & Kopple, K. D. (2002). Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. 2615–2623. https://doi.org/10.1021/jm020017nWalters, W. P. (2012). Expert Opinion on Drug Discovery Going further than Lipinski ’ s rule in drug design Going further than Lipinski ’ s rule in drug design. 0441. https://doi.org/10.1517/17460441.2012.648612Watanabe, M., Maernura, K., Kanbara, K., Tamayama, T., & Hayasaki, H. (2002). GABA and GABA Receptors in the Central Nervous System and Other Organs. 213.Zhu, H., Martin, T. M., Ye, L., Sedykh, A., Young, D. M., & Tropsha, A. (2009). Quantitative Structure - Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure. 1913–1921.síntesis multicomponente, cribado virtual y evaluación de la actividad tranquilizante de nuevos compuestos tiazepínicos, tiazolidínicos y quinolínicosAdministradoresBibliotecariosConsejerosEstudiantesGrupos comunitariosInvestigadoresMaestrosPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84510/3/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD53ORIGINAL1143381986.2023.pdf1143381986.2023.pdfTesis de Maestría en Ciencias - Farmacologíaapplication/pdf8762139https://repositorio.unal.edu.co/bitstream/unal/84510/4/1143381986.2023.pdf0b66734afa08ee93d0d084067da7149aMD54THUMBNAIL1143381986.2023.pdf.jpg1143381986.2023.pdf.jpgGenerated 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