Diseño in-silico y sintesis de posibles candidatos para el tratamiento de leucemia linfoblástica aguda apartir de diseños qsar y modelos de acoplamiento molecular

Cristhian Camilo, Alvarez Gómez

Diseño in-silico y sintesis de posibles candidatos para el tratamiento de leucemia linfoblástica aguda apartir de diseños qsar y modelos de acoplamiento molecular

dc.contributor.advisor	James Oswaldo, Guevara Pulido
dc.contributor.author	Cristhian Camilo, Alvarez Gómez
dc.contributor.orcid	Cristhian Camilo, Alvarez Gómez [0009-0007-5059-3392]
dc.date.accessioned	2024-11-27T00:23:52Z
dc.date.available	2024-11-27T00:23:52Z
dc.date.issued	2024-11
dc.description.abstract	La leucemia linfoblástica aguda (LLA) es altamente prevalente tanto en poblaciones pediátricas como en adultas. Aunque existen 156 tratamientos contra el cáncer basados en pequeñas moléculas aprobados, solo cinco están dirigidos a todos los tipos de leucemia. Sin embargo, estos tratamientos presentan una baja adherencia debido a los efectos secundarios. Es urgente encontrar mejores opciones terapéuticas para la LLA. Nuestro estudio ofrece una solución potencial. Diseñamos más de 50 análogos de carbamazepina mediante una combinación de métodos de diseño de fármacos basados en ligandos y en estructura. Entre estos análogos, seleccionamos el análogo CR80, que mostró valores predichos de -8,66 kcal/mol frente a la beta-tubulina y un IC50 estimado de ± 800 nM. Además, presentó valores seguros de LogP y toxicidad para su evaluación in vitro. El compuesto CR80 fue sintetizado con un rendimiento del 50% y evaluado in vitro contra la línea celular U-937, donde mostró un índice de selectividad de dos, lo que lo convierte en un candidato prometedor para evaluaciones in vivo.
dc.description.abstractenglish	Acute lymphoblastic leukemia (ALL) is highly prevalent in both pediatric and adult populations. Although 156 approved cancer treatments are based on small molecules, only five are for all leukemia types. However, these treatments have low adherence due to side effects. It is urgent to find better treatments for ALL. Our study offers a potential solution. We designed more than 50 analogs to carbamazepine using a combination of ligand-based and structure-based drug design. Among these analogs, we selected the CR80 analog, which had predicted values of -8.66 kcal/mol against beta-tubulin and an expected +- 800 nM of IC50. It also exhibited safe LogP and toxicity values for in vitro evaluation. CR80 was synthesized with a yield of 50% and was evaluated in vitro against the U-937 cell line. It showed a selectivity index of two, which makes it a promising candidate for in vivo evaluations.
dc.description.degreelevel	Pregrado	spa
dc.description.degreelevel	Químico Farmacéutico	spa
dc.format.mimetype	application/pdf
dc.identifier.instname	Universidad El Bosque	spa
dc.identifier.reponame	reponame:Repositorio Institucional Universidad El Bosque	spa
dc.identifier.repourl	repourl:https://repositorio.unbosque.edu.co
dc.identifier.uri	https://hdl.handle.net/20.500.12495/13377
dc.language.iso	en
dc.publisher.faculty	Facultad de Ciencias	spa
dc.publisher.grantor	Universidad El Bosque	spa
dc.publisher.program	Química Farmacéutica	spa
dc.relation.references	1. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J [Internet]. 2017;7(6):e577–e577. Disponible en: http://dx.doi.org/10.1038/bcj.2017.53
dc.relation.references	2. Manuals MSD. Acute Lymphoblastic Leukemia (ALL) - acute Lymphoblastic Leukemia (ALL) - MSD manual professional edition. 2016.
dc.relation.references	3. Li R, Ma X-L, Gou C, Tse WKF. Editorial: Novel small molecules in targeted cancer therapy. Front Pharmacol [Internet]. 2023;14:1272523. Disponible en: http://dx.doi.org/10.3389/fphar.2023.1272523
dc.relation.references	4. Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, et al. Cancer chemotherapy and beyond Current status, drug candidates, associated risks and pro-gress in targeted therapeutics. Genes Dis [Internet]. 2023;10(4):1367–401. Disponible en: http://dx.doi.org/10.1016/j.gendis.2022.02.007
dc.relation.references	6. Schmiegelow K, Attarbaschi A, Barzilai S, Escherich G, Frandsen TL, Halsey C, et al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. Lancet Oncol [Internet]. 2016;17(6):e231–9. Disponible en: http://dx.doi.org/10.1016/S1470-2045(16)30035-3
dc.relation.references	6. Schmiegelow K, Attarbaschi A, Barzilai S, Escherich G, Frandsen TL, Halsey C, et 396 al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leu-397 kaemia treatment: a Delphi consensus. Lancet Oncol [Internet]. 2016;17(6):e231–9. Dis-398 ponible en: http://dx.doi.org/10.1016/S1470-2045(16)30035-3
dc.relation.references	7. Kuhlen M, Kunstreich M, Gökbuget N, Escherich G. Osteonekrosen – gravie-rende Therapiefolge bei akuter lymphoblastischer Leukämie. Orthopadie (Heidelb) [Internet]. 2022;51(10):792–9. Disponible en: http://dx.doi.org/10.1007/s00132-022-04301-1
dc.relation.references	8. Aytaç S, Gümrük F, Cetin M, Tuncer M, Yetgin S. Acral erythema with bullous formation: a side effect of chemotherapy in a child with acute lymphoblastic leukemia. Turk J Pediatr. 2010;52(2):211–4.
dc.relation.references	9. Yu W, MacKerell AD Jr. Computer-aided drug design methods. En: Methods in Molecular Biology. New York, NY: Springer New York; 2017. p. 85–106.
dc.relation.references	10. Vemula D, Jayasurya P, Sushmitha V, Kumar YN, Bhandari V. CADD, AI and ML in drug discovery: A comprehensive review. Eur J Pharm Sci [Internet]. 2023;181(106324):106324. Disponible en: http://dx.doi.org/10.1016/j.ejps.2022.106324
dc.relation.references	11. Niazi SK, Mariam Z. Computer-Aided Drug Design and drug discovery: A prospective analysis. Pharmaceuticals (Basel) [Internet]. 2023;17(1):22. Disponible en: http://dx.doi.org/10.3390/ph17010022
dc.relation.references	12. Silverman DA, Chapron DJ. Lymphopenic effect of carbamazepine in a patient with chronic lymphocytic leukemia. Ann Pharmacother [Internet]. 1995;29(9):865–7. Disponible en: http://dx.doi.org/10.1177/106002809502900906
dc.relation.references	13. Meng Q, Chen X, Sun L, Zhao C, Sui G, Cai L. Carbamazepine promotes Her-2 protein degradation in breast cancer cells by modulating HDAC6 activity and acetyla-tion of Hsp90. Mol Cell Biochem [Internet]. 2011;348(1– 2):165–71. Disponible en: http://dx.doi.org/10.1007/s11010-010-0651-y
dc.relation.references	14. Zhao reported that CBZ has an affinity for the Frizzled FZD8 receptor (via Wnt); inhibiting this receptor decreases bone remodeling and promotes the apoptosis of bone cells, which are the origin of some types of leukemia. 2020.
dc.relation.references	15. Fonseca-Benítez V, Acosta-Guzmán P, Sánchez JE, Alarcón Z, Jiménez RA, Guevara-Pulido J. Design and evaluation of NSAID derivatives as AKR1C3 inhibitors for breast cancer treatment through computer-aided drug design and in vitro analysis. Molecules [Internet]. 2024;29(8). Disponible en: http://dx.doi.org/10.3390/molecules29081802
dc.relation.references	16. Jaramillo DN, Millán D, Guevara-Pulido J. Design, synthesis and cytotoxic evaluation of a selective serotonin reuptake inhibitor (SSRI) by virtual screening. Eur J Pharm Sci [Internet]. 2023;183(106403):106403. Disponible en: http://dx.doi.org/10.1016/j.ejps.2023.106403
dc.relation.references	17. Prieto M, Niño A, Acosta-Guzmán P, Guevara-Pulido J. Design and synthesis of a potential selective JAK-3 inhibitor for the treatment of rheumatoid arthritis using predictive QSAR models. Inform Med Unlocked [Internet]. 2024;45(101464):101464. Disponible en: http://dx.doi.org/10.1016/j.imu.2024.101464
dc.relation.references	18. Atherton J, Luo Y, Xiang S, Yang C, Rai A, Jiang K, et al. Structural determinants of microtubule minus end preference in CAMSAP CKK domains. Nat Commun [In-ternet]. 2019;10(1). Disponible en: http://dx.doi.org/10.1038/s41467-019-13247-6
dc.relation.references	19. Huey R, Morris GM, Forli S. The Scripps Research Institute Molecular Graphics Laboratory; 2012. Using AutoDock 4 and AutoDock Vina with AutoDockTools: A Tu-torial.
dc.relation.references	20. Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminform [Internet]. 2012;4(1):17. Disponible en: http://dx.doi.org/10.1186/1758-2946-4-17
dc.relation.references	21. Guevara-Pulido J, Jiménez RA, Morantes SJ, Jaramillo DN, Acosta-Guzmán P. Design, synthesis, and development of 4‐[(7‐chloroquinoline‐4‐yl)amino]phenol as a potential SARS‐CoV‐2 Mpro inhibitor. ChemistrySelect [Internet]. 2022;7(15). Dis-ponible en: http://dx.doi.org/10.1002/slct.202200125
dc.relation.references	22. Yap CW. PaDEL-descriptor: an open source software to calculate molecular descriptors and fingerprints. J Comput Chem [Internet]. 2011;32(7):1466–74. Disponible en: http://dx.doi.org/10.1002/jcc.21707
dc.relation.references	23. Alexander DLJ, Tropsha A, Winkler DA. Beware of R2: Simple, Unambiguous Assessment of the Prediction Environmental Science: Water Research & Technology Paper Accuracy of QSAR and QSPR Models. J Chem Inf Model. 2015;(7):1316–22.
dc.relation.references	24. Golbraikh A, Tropsha A. Beware of q2! J Mol Graph Model [Internet]. 2002;20(4):269–76. Disponible en: http://dx.doi.org/10.1016/s1093-3263(01)00123-1
dc.relation.references	25. Buncherd H, Hongmanee S, Saechan C, Tansila N, Thanapongpichat S, Wanichsuwan W, et al. Latex C-serum from Hevea brasiliensis induces apoptotic cell death in a leukemic cell line. Mol Biol Rep [Internet]. 2023;50(9):7515–25. Disponible en: http://dx.doi.org/10.1007/s11033-023-08687-9
dc.relation.references	26. Fu L, Shi S, Yi J, Wang N, He Y, Wu Z, et al. ADMETlab 3.0: an updated com-prehensive online ADMET prediction platform enhanced with broader coverage, im-proved performance, API functionality and decision support. Nucleic Acids Res [In-ternet]. 2024;52(W1):W422–31. Disponible en: http://dx.doi.org/10.1093/nar/gkae236
dc.relation.references	27. Majcher U, Klejborowska G, Moshari M, Maj E, Wietrzyk J, Bartl F, et al. Anti-proliferative activity and molecular docking of novel double-modified colchicine de-rivatives. Cells [Internet]. 2018;7(11):192. Disponible en: http://dx.doi.org/10.3390/cells7110192
dc.relation.references	28. Ni H, Li C, Shi X, Hu X, Mao H. Visible-light-promoted Fe(III)-catalyzed N-H alkylation of amides and Nheterocycles. J Org Chem [Internet]. 2022;87(15):9797–805. Disponible en: http://dx.doi.org/10.1021/acs.joc.2c00854
dc.relation.references	29. Sugiura M, Hagio H, Hirabayashi R, Kobayashi S. Lewis acid-catalyzed ring-opening reactions of semicyclic N,O-acetals possessing an exocyclic nitrogen atom: mechanistic aspect and application to piperidine alkaloid synthesis. J Am Chem Soc [Internet]. 2001;123(50):12510–7. Disponible en: http://dx.doi.org/10.1021/ja0170448
dc.relation.references	30. Deng Y, Hu Z, Xue J, Yin J, Zhu T, Liu S. Visible-Light-Promoted α-C (sp3)-H Ami-nation of Ethers with Azoles and Amides. Organic Letters. 2024;26(4):933–8.
dc.rights.accessrights	info:eu-repo/semantics/closedAccess
dc.rights.accessrights	http://purl.org/coar/access_right/c_14cb
dc.rights.local	Acceso cerrado	spa
dc.subject	Antitumoral
dc.subject	LLA (Leucemia Linfoblástica Aguda)
dc.subject	CADD (Diseño de Fármacos Asistido por Computadora)
dc.subject	Carbamazepina
dc.subject.ddc	615.19
dc.subject.keywords	Antitumoral
dc.subject.keywords	ALL
dc.subject.keywords	CADD (Computer-Aided Drug Design)
dc.subject.keywords	Carbamazepine
dc.title	Diseño in-silico y sintesis de posibles candidatos para el tratamiento de leucemia linfoblástica aguda apartir de diseños qsar y modelos de acoplamiento molecular
dc.title.translated	Design, synthesis, and in vitro evaluation of a carbamazepine 2 derivative with antitumor potential in a model of acute lym-3 phoblastic leukemia
dc.type.coar	https://purl.org/coar/resource_type/c_7a1f
dc.type.coarversion	https://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.driver	info:eu-repo/semantics/bachelorThesis
dc.type.hasversion	info:eu-repo/semantics/acceptedVersion
dc.type.local	Tesis/Trabajo de grado - Monografía - Pregrado