J. Pharm. Pharmacogn. Res., vol. 12, no. 5, pp. 881-891, Sep-Oct 2024.
DOI: https://doi.org/10.56499/jppres23.1740_12.5.881
Original Article
Epidermal growth factor receptor mutant T790M-L858R-V948R inhibitor from Calophyllum inophyllum L. leaf as potential non-small cell lung cancer drugs
[Inhibidor del receptor del factor de crecimiento epidérmico mutante T790M-L858R-V948R de la hoja de Calophyllum inophyllum L. como posible fármaco contra el cáncer de pulmón de células no pequeñas]
Precella Silvia, Jeremi Ongko, Yulanda Antonius*
Faculty of Biotechnology, University of Surabaya, Raya Kalirungkut, Surabaya 60293, Indonesia.
*E-mail: yulandaantonius@staff.ubaya.ac.id
Abstract
Context: Non-Small Cell Lung Cancer (NSCLC) is the most common lung cancer type, with 80-85% prevalence. Usually, NSCLC is treated by chemotherapy and radiotherapy in collaboration with gefitinib or other anticancer drugs. Those treatments have many adverse effects, such as shortness of breath, bleeding, fever, hair loss, and radiation pneumonitis. Lack of treatment options and numerous mutations greatly contribute to lung cancer's shocking death toll. Therefore, potential EGFR mutant inhibitors need to be analyzed.
Aims: To identify potential inhibitors of an epidermal growth factor receptor (EGFR) mutant derived from Calophyllum inophyllum L. leaf using an in silico approach.
Methods: In silico analysis and literature study were carried out. Secondary metabolite compounds from C. inophyllum were obtained through the PubChem database, and their biological activity and ADMET were analyzed. Molecular docking with EGFR wild-type (5FED) and mutant (5HG7) was carried out using PyRx. Furthermore, amino acid residues were analyzed using Discovery Studio.
Results: Based on overall screening and molecular docking, a non-toxic compound with a low binding affinity with EGFR mutant protein is 4-[2-(4-nitrophenyl)ethylcarbamoyl]benzenesulfonyl. Moreover, interactions and hydrogen bonds at Ala743, Gly796, Leu718, Phe856, Leu844, and Val726 are known to play a crucial role in ATP binding inhibition toward the tyrosine kinase domain, resulting in EGFR mutant inhibition.
Conclusions: 4-[2-(4-nitrophenyl)ethylcarbamoyl]benzenesulfonyl is one of the potential candidates as an EGFR mutant protein by ATP binding inhibition. However, in vitro and in vivo research needs to be performed to confirm these results.
Keywords: anticancer drug; lung cancer; NSCLC; secondary metabolites; virtual screening.
Resumen
Contexto: El cáncer de pulmón no microcítico (CPNM) es el tipo de cáncer de pulmón más frecuente, con una prevalencia del 80-85%. Por lo general, el CPNM se trata mediante quimioterapia y radioterapia en colaboración con gefitinib u otros medicamentos contra el cáncer. Esos tratamientos tienen muchos efectos adversos, como dificultad para respirar, hemorragias, fiebre, caída del cabello y neumonitis por radiación. La falta de opciones de tratamiento y las numerosas mutaciones contribuyen en gran medida a que el cáncer de pulmón se cobre un número de víctimas alarmante. Por lo tanto, es necesario analizar los posibles inhibidores mutantes del EGFR.
Objetivos: Identificar inhibidores potenciales del receptor del factor de crecimiento epidérmico (EGFR) mutante derivado de la hoja de Calophyllum inophyllum L. mediante un enfoque in silico.
Métodos: Se llevó a cabo un análisis in silico y un estudio bibliográfico. Los compuestos de metabolitos secundarios de C. inophyllum se obtuvieron a través de la base de datos PubChem, y se analizó su actividad biológica y ADMET. El acoplamiento molecular con el EGFR de tipo salvaje (5FED) y mutante (5HG7) se llevó a cabo utilizando PyRx. Además, se analizaron los residuos de aminoácidos con Discovery Studio.
Resultados: Basándose en el cribado general y el acoplamiento molecular, un compuesto no tóxico con una baja afinidad de unión con la proteína mutante EGFR es 4-[2-(4-nitrofenil)etilcarbamoil]bencenosulfonil. Además, se sabe que las interacciones y los enlaces de hidrógeno en Ala743, Gly796, Leu718, Phe856, Leu844 y Val726 desempeñan un papel crucial en la inhibición de la unión del ATP hacia el dominio tirosina cinasa, lo que resulta en la inhibición del mutante EGFR.
Conclusiones: El 4-[2-(4-nitrofenil)etilcarbamoil]bencenosulfonil es uno de los candidatos potenciales como proteína mutante del EGFR por inhibición de la unión al ATP. Sin embargo, es necesario realizar investigaciones in vitro e in vivo para confirmar estos resultados.
Palabras Clave: cáncer de pulmón; CPNM; cribado virtual; fármaco anticanceroso; metabolitos secundarios.
Citation Format: Silvia P, Ongko J, Antonius Y (2024) Epidermal growth factor receptor mutant T790M-L858R-V948R inhibitor from Calophyllum inophyllum L. leaf as potential non-small cell lung cancer drugs. J Pharm Pharmacogn Res 12(5): 881–891. https://doi.org/10.56499/jppres23.1740_12.5.881
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