Acoplamiento molecular de imidazoles psudopeptídicos como inhibidores selectivos contra la enzima CYP51
Palavras-chave:
acoplamiento molecular; CYP51, imidazoles pseudopeptídicos; índice de selectividad.Resumo
La familia P450, y en especial la proteína CYP51, es blanco común para el diseño de fármacos antimicóticos y antiprotozoarios. Diseñar nuevos fármacos efectivos contra
estos patógenos es una necesidad y un reto para la comunidad científica. Con este objetivo se evalúan mediante acoplamiento molecular de cinco esquemas de imidazoles arilsustituidos e imidazoles pseudopeptídicos contra proteínas CYP51 de distintos patógenos y contra la similar proteína humana para estimar su selectividad. Una vez
realizado estos cálculos se arriba a que ninguno de los compuestos estudiados parece ser un inhibidor efectivo contra CYP51-L.infantum. Sin embargo, para todas las restantes proteínas se obtienen menores puntuaciones normalizadas del acoplamiento, fundamentalmente para los esquemas 1 y 3. Dada la geometría de los complejos
proteína-ligado formados los esquemas 2 y 4 se muestran más selectivos que los esquemas 1, 3 y 5. Sin embargo, los mayores valores de selectividad estimada se obtienen para los esquemas 1 y 3 contra CYP51-C.glabrata y para el esquema 1 contra CYP51-N.fowleri. De manera general, se constata la relación directa entre la estabilidad del complejo proteína-ligado con la interacción directa del ligando con catión Fe2+ del grupo heme, la cual aporta estabilidad a la unión.
Referências
LEPESHEVA, G. I. AND M. R. WATERMAN "CYP51—the omnipotent P450".
Molecular and cellular endocrinology, 2004, 215(1-2), 165-170.
https://doi.org/10.1016/j.mce.2003.11.016.
LEPESHEVA, G. I., T. Y. HARGROVE, Y. KLESHCHENKO, W. D. NES, et al.
"CYP51: A major drug target in the cytochrome P450 superfamily". Lipids, 2008,
(12), 1117-1125. https://doi.org/10.1007/s11745-008-3225-y.
CHOI, J. Y., L. M. PODUST AND W. R. ROUSH "Drug strategies targeting CYP51
in neglected tropical diseases". Chemical Reviews, 2014, 114(22), 11242-11271.
https://doi.org/10.1021/cr5003134.
HARGROVE, T. Y., K. KIM, M. D. N. C. SOEIRO, C. F. DA SILVA, et al. "CYP51
structures and structure-based development of novel, pathogen-specific inhibitory
scaffolds". International Journal for Parasitology: Drugs and Drug Resistance, 2012,
, 178-186. https://doi.org/10.1016/j.ijpddr.2012.06.001.
WARRILOW, A. G., C. L. PRICE, J. E. PARKER, N. J. ROLLEY, et al. "Azole
antifungal sensitivity of sterol 14α-demethylase (CYP51) and CYP5218 from
Malassezia globosa". Scientific reports, 2016, 6(1), 1-10.
https://doi.org/10.1038/srep27690.
ZHANG, J., L. LI, Q. LV, L. YAN, et al. "The fungal CYP51s: Their functions,
structures, related drug resistance, and inhibitors". Frontiers in microbiology, 2019, 10,
https://doi.org/10.3389/fmicb.2019.00691.
ZHANG, H.-Z., L.-L. GAN, H. WANG AND C.-H. ZHOU "New progress in azole
compounds as antimicrobial agents". Mini reviews in medicinal chemistry, 2017, 17(2),
-166. https://doi.org/10.2174/1389557516666160630120725.
WARRILOW, A. G., J. E. PARKER, C. L. PRICE, E. P. GARVEY, et al. "The
tetrazole VT-1161 is a potent inhibitor of Trichophyton rubrum through its inhibition of
T. rubrum CYP51". Antimicrobial agents and chemotherapy, 2017, 61(7), e00333-
https://doi.org/10.1128/aac.00333-17.
VERMA, A. K., A. MAJID, M. HOSSAIN, S. AHMED, et al. "Identification of 1, 2,
-triazine and its derivatives against Lanosterol 14-demethylase (CYP51) property of
Candida albicans: Influence on the development of new antifungal therapeutic
strategies". Frontiers in medical technology, 2022, 16.
https://doi.org/10.3389/fmedt.2022.845322.
DOYLE, P. S., C.-K. CHEN, J. B. JOHNSTON, S. D. HOPKINS, et al. "A
nonazole CYP51 inhibitor cures Chagas’ disease in a mouse model of acute infection".
Antimicrobial agents and chemotherapy, 2010, 54(6), 2480-2488.
https://doi.org/10.1128/aac.00281-10.
HASSAN, E. A., I. A. SHEHADI, A. M. ELMAGHRABY, H. M. MOSTAFA, et
al. "Synthesis, molecular docking analysis and in vitro biological evaluation of some
new heterocyclic scaffolds-based indole moiety as possible antimicrobial agents".
Frontiers in molecular biosciences, 2022, 1238.
https://doi.org/10.3389/fmolb.2021.775013.
COTUÁ, J., H. LLINÁS AND S. COTES "Virtual Screening Based on QSAR and
Molecular Docking of Possible Inhibitors Targeting Chagas CYP51". Journal of
Chemistry, 2021, 2021. https://doi.org/10.1155/2021/6640624
WARRILOW, A. G., J. E. PARKER, D. E. KELLY AND S. L. KELLY "Azole
affinity of sterol 14α-demethylase (CYP51) enzymes from Candida albicans and Homo
sapiens". Antimicrobial agents and chemotherapy, 2013, 57(3), 1352-1360.
https://doi.org/10.1128/aac.02067-12.
IRANNEJAD, H., S. EMAMI, H. MIRZAEI AND S. M. HASHEMI "In silico
prediction of ATTAF-1 and ATTAF-2 selectivity towards human/fungal lanosterol 14α-
demethylase using molecular dynamic simulation and docking approaches". Informatics
in Medicine Unlocked, 2020, 20, 100366. https://doi.org/10.1016/j.imu.2020.100366.
BERMAN, H. M., T. BATTISTUZ, T. N. BHAT, W. F. BLUHM, et al. "The
protein data bank". Acta Crystallographica Section D: Biological Crystallography,
, 58(6), 899-907. https://doi.org/10.1107/S0907444902003451.
O'BOYLE, N. M., M. BANCK, C. A. JAMES, C. MORLEY, et al. "Open Babel:
An open chemical toolbox". Journal of cheminformatics, 2011, 3(1), 1-14.
https://doi.org/10.1186/1758-2946-3-33.
PETTERSEN, E. F., T. D. GODDARD, C. C. HUANG, G. S. COUCH, et al.
"UCSF Chimera—a visualization system for exploratory research and analysis".
Journal of computational chemistry, 2004, 25(13), 1605-1612.
https://doi.org/10.1002/jcc.20084.
SOLIS-VASQUEZ, L., A. F. TILLACK, D. SANTOS-MARTINS, A. KOCH, et al.
"Benchmarking the performance of irregular computations in AutoDock-GPU
molecular docking". Parallel Computing, 2022, 109, 102861.
https://doi.org/10.1016/j.parco.2021.102861.
LASKOWSKI, R. A. AND M. B. SWINDELLS. LigPlot+: multiple ligand–protein
interaction diagrams for drug discovery. In.: ACS Publications, 2011.
https://doi.org/10.1021/ci200227u.
DA SILVA, J. K. R., P. L. B. FIGUEIREDO, K. G. BYLER AND W. N. SETZER
"Essential oils as antiviral agents, potential of essential oils to treat SARS-CoV-2
infection: An in-silico investigation". International journal of molecular sciences,
, 21(10), 3426. https://doi.org/10.3390/ijms21103426.
BELL, E. W. AND Y. ZHANG "DockRMSD: an open-source tool for atom
mapping and RMSD calculation of symmetric molecules through graph isomorphism".
Journal of cheminformatics, 2019, 11(1), 1-9. https://doi.org/10.1186/s13321-019-
-7.
ARBA, M., S. IHSAN AND D. H. TJAHJONO "In silico study of porphyrin-
anthraquinone hybrids as CDK2 inhibitor". Computational Biology and Chemistry,
, 67, 9-14. https://doi.org/10.1016/j.compbiolchem.2016.12.005.
VARGAS, J. A. R., A. G. LOPEZ, M. C. PIÑOL AND M. FROEYEN "Molecular
docking study on the interaction between 2-substituted-4, 5-difuryl Imidazoles with
different Protein Target for antileishmanial activity". Journal of Applied
Pharmaceutical Science, 2018, 8(3), 014-022.
http://dx.doi.org/10.7324/JAPS.2018.8303.
HEVENER, K. E., W. ZHAO, D. M. BALL, K. BABAOGLU, et al. "Validation of
Molecular Docking Programs for Virtual Screening against Dihydropteroate Synthase".
J Chem Inf Model, 2009, 49(2), 444-460. https://doi.org/10.1021/ci800293n.
ZINAD, D. S., A. MAHAL, S. SISWODIHARDJO, M. R. F. PRATAMA, et al.
"3D-Molecular Modeling, Antibacterial Activity and Molecular Docking Studies of
Some Imidazole Derivatives". Egyptian Journal of Chemistry, 2021, 64(1), 93-105.
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