MDM2 protein inhibition of Aucklandia costus compounds

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J. Pharm. Pharmacogn. Res., vol. 12, no. 4, pp. 748-758, Jul-Aug 2024. DOI: https://doi.org/10.56499/jppres23.1910_12.4.748 Original Article Anticancer activity of Aucklandia costus Falc. terpenes: Targeting MDM2 protein inhibition for therapeutic advancements [Actividad anticancerígena de los terpenos de Aucklandia costus Falc.: Inhibición de la proteína MDM2 para avances terapéuticos] Theresia Indah Budhy1, Ira Arundina2*, Anis Irmawati2, Sidarningsih2, … Continue reading MDM2 protein inhibition of Aucklandia costus compounds

J. Pharm. Pharmacogn. Res., vol. 12, no. 4, pp. 748-758, Jul-Aug 2024.

DOI: https://doi.org/10.56499/jppres23.1910_12.4.748

Original Article

Anticancer activity of Aucklandia costus Falc. terpenes: Targeting MDM2 protein inhibition for therapeutic advancements

[Actividad anticancerígena de los terpenos de Aucklandia costus Falc.: Inhibición de la proteína MDM2 para avances terapéuticos]

Theresia Indah Budhy1, Ira Arundina2*, Anis Irmawati2, Sidarningsih2, Meircurius Dwi Condro Surboyo3, Cecillia Octavianni Raharjo4, Ciptantyo Septyan Akbar4, Malika Qadira Rahmalia4

1Department of Oral Pathology and Maxillofacial, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60132, Indonesia.

2Department of Oral Biology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60132, Indonesia.

3Department of Oral Medicine, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60132, Indonesia.

4Undergraduate Student, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60132, Indonesia.

*E-mail: ira-a@fkg.unair.ac.id

Abstract

Context: Protein 53 (p53) is a well-known tumor suppressor protein, while murine double minute 2 (MDM2) acts as a negative regulator of p53, leading to p53 inactivation and cancer development. Aucklandia costus Falc. or Saussurea lappa contains bioactive compounds, particularly terpenoids, known for their anticancer activity against various cancer cells. Targeting the p53-MDM2 protein interaction and inhibiting MDM2 are crucial strategies in cancer therapy.

Aims: To analyze the anticancer properties of A. costus terpenes against MDM2 protein.

Methods: The compounds costunolide, dehydrocostus lactone, lappadilactone, and cynaropicrin were docked with MDM2 (PDB ID: 4HG7) using AutoDockTools 1.5.6. Additionally, the physicochemical, pharmacokinetic, and toxicity properties were predicted using pkCSM.

Results: Lappadilactone exhibited the highest binding energy value, surpassing both the control and the native ligand. Following lappadilactone, cynaropicrin, costunolide, and dehydrocostus lactone displayed decreasing binding energies. When assessing ADMET properties with pkCSM, all compounds exhibited good permeability, suggesting their ability to penetrate intestinal cell membranes, and showed no signs of hepatotoxicity.

Conclusions: Lappadilactone emerges as a promising candidate with high intestinal absorption, distinctive distribution characteristics, and a lack of mutagenic or hepatotoxic effects.

Keywords: ADMET; Aucklandia costus; cancer; docking; MDM2; Saussurea lappa.

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Resumen

Contexto: La proteína 53 (p53) es una conocida proteína supresora de tumores, mientras que la doble minúscula murina 2 (MDM2) actúa como regulador negativo de p53, lo que conduce a su inactivación y al desarrollo del cáncer. Aucklandia costus Falc. o Saussurea lappa contiene compuestos bioactivos, en particular terpenoides, conocidos por su actividad anticancerígena contra diversas células cancerosas. Dirigirse a la interacción proteína p53-MDM2 e inhibir MDM2 son estrategias cruciales en la terapia del cáncer.

Objetivos: Analizar las propiedades anticancerígenas de los terpenos de A. costus frente a la proteína MDM2.

Métodos: Los compuestos costunolide, dehydrocostus lactone, lappadilactone, y cynaropicrin fueron acoplados a MDM2 (PDB ID: 4HG7) usando AutoDockTools 1.5.6. Además, se analizaron las propiedades fisicoquímicas y moleculares de los terpenos. Además, se predijeron las propiedades fisicoquímicas, farmacocinéticas y de toxicidad utilizando pkCSM.

Resultados: Lappadilactona mostró el mayor valor de energía de unión, superando tanto al control como al ligando nativo. Tras la lappadilactona, la cinaropicrina, la costunolida y la lactona dehidrocostus mostraron energías de unión decrecientes. Al evaluar las propiedades ADMET con pkCSM, todos los compuestos mostraron una buena permeabilidad, lo que sugiere su capacidad para penetrar en las membranas celulares intestinales, y no mostraron signos de hepatotoxicidad.

Conclusiones: La lapadilactona emerge como un candidato prometedor con alta absorción intestinal, características de distribución distintivas y ausencia de efectos mutagénicos o hepatotóxicos.

Palabras Clave: ADMET; Aucklandia costus; cáncer; docking; MDM2; Saussurea lappa.

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Citation Format: Budhy TI, Arundina I, Irmawati A, Sidarningsih, Surboyo MDC, Raharjo CO, Akbar CS, Rahmalia MQ (2024) Anticancer activity of Aucklandia costus Falc. terpenes: Targeting MDM2 protein inhibition for therapeutic advancements. J Pharm Pharmacogn Res 12(4): 748–758. https://doi.org/10.56499/jppres23.1910_12.4.748
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