J. Pharm. Pharmacogn. Res., vol. 12, no. 2, pp. 264-285, Mar-Apr 2024.

DOI: https://doi.org/10.56499/jppres23.1719_12.2.264

Original Article

Activity of propolis compounds as potential MMP1 and MMP2 inhibitors by in silico studies in wound healing application

[Actividad de compuestos de propóleos como inhibidores potenciales de MMP1 y MMP2 mediante estudios in silico sobre la cicatrización de heridas]

Adzani Gaisani Arda^1,2, Putri Hawa Syaifie^1*, Donny Ramadhan^1,3, Muhammad Miftah Jauhar^1,4, Dwi Wahyu Nugroho¹, Nofa Mardia Ningsih Kaswati¹, Alfian Noviyanto^1,5, Mega Safihtri⁶, Nurul Taufiqu Rochman⁷, Dimas Andrianto⁶, Etik Mardliyati^8*

¹Nano Center Indonesia, Jl. Raya PUSPIPTEK, South Tangerang, Banten, 15314, Indonesia.

²Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary.

³Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), Cibinong Science Center, West Java, 16911, Indonesia.

⁴Biomedical Engineering, Graduate School of Universitas Gadjah Mada, Sleman 55281, Yogyakarta, Indonesia.

⁵Department of Mechanical Engineering, Mercu Buana University, Jakarta 11650, Indonesia.

⁶Department of Biochemistry, Bogor Agricultural University, Jl. Raya Dramaga IPB Campus Dramaga Bogor, Bogor, 16680, Indonesia.

⁷Research Center for Advanced Material, National Research and Innovation Agency (BRIN), PUSPIPTEK, South Tangerang, Banten, 15314, Indonesia.

⁸Research Center for Vaccine and Drug, National Research and Innovation Agency (BRIN), Cibinong Science Center, West Java, 16911, Indonesia.

*E-mail: etik002@brin.go.id

Abstract

Context: Matrix metalloproteinases (MMPs) play a critical role in wound healing, with higher levels seen in chronic wounds, delaying healing. Since ancient times, propolis has been widely used for traditional wound healing. However, there is still limited research on MMP1 and MMP12.

Aims: To evaluate new candidates of propolis compounds for targeting MMP1 and MMP12 using in silico studies supported by experimental screening using LC-MS/MS quadrupole-time of flight (QTOF).

Methods: Compounds in propolis were screened using LC-MS/MS QTOF. The 3D structure of all compounds in propolis and protein targets was prepared in Autodock and Biovia Discovery Studio. The molecular docking of all compounds in propolis was carried out using Autodock on PyRx 0.9. Drug-likeness and ADMET analysis of selected compounds in propolis with the lowest affinity were observed. Lastly, molecular dynamic simulations of the best compounds in propolis were conducted using the GROMACS 2020 package.

Results: Eleven flavonoid and phenolic compounds were identified in propolis using LC-MS/MS QTOF analysis. Molecular docking simulations showed that licoflavone A and pinostrobin exhibited the lowest binding affinity to MMP1 and MMP12, respectively. Molecular dynamic simulations revealed that licoflavone A formed a more stabilized complex with MMP1, while pinostrobin formed a more stabilized complex with MMP12 than the native ligand.

Conclusions: This study revealed new candidates for MMP1 and MMP12 inhibitors from propolis compounds that can enhance wound healing. It is hoped that the evidence gathered in this study provides crucial new information in exploring new wound-healing medications.

Keywords: matrix metalloproteinases; molecular docking simulation; molecular dynamics simulation; propolis; wound healing.

Resumen

Contexto: Las metaloproteinasas de la matriz (MMP) desempeñan un papel fundamental en la cicatrización de las heridas, observándose niveles más elevados en las heridas crónicas, lo que retrasa la cicatrización. Desde la antigüedad, el propóleo se ha utilizado ampliamente para la cicatrización tradicional de heridas. Sin embargo, la investigación sobre las MMP1 y MMP12 sigue siendo limitada.

Objetivos: Evaluar nuevos candidatos de compuestos de propóleo para atacar MMP1 y MMP12 mediante estudios in silico apoyados por cribado experimental utilizando LC-MS/MS cuadrupolo-tiempo de vuelo (QTOF).

Métodos: Los compuestos del propóleo se analizaron mediante LC-MS/MS QTOF. La estructura 3D de todos los compuestos del propóleo y de las proteínas diana se preparó en Autodock y Biovia Discovery Studio. El acoplamiento molecular de todos los compuestos del propóleo se llevó a cabo utilizando Autodock en PyRx 0.9. Se observó la afinidad a fármacos y el análisis ADMET de los compuestos seleccionados en el propóleo con menor afinidad. Por último, se realizaron simulaciones de dinámica molecular de los mejores compuestos del propóleo con el paquete GROMACS 2020.

Resultados: Se identificaron once compuestos flavonoides y fenólicos en el propóleo mediante análisis LC-MS/MS QTOF. Las simulaciones de acoplamiento molecular mostraron que la licoflavona A y la pinostrobina presentaban la menor afinidad de unión con la MMP1 y la MMP12, respectivamente. Las simulaciones de dinámica molecular revelaron que la licoflavona A formaba un complejo más estabilizado con la MMP1, mientras que la pinostrobina formaba un complejo más estabilizado con la MMP12 que el ligando nativo.

Conclusiones: Este estudio reveló nuevos candidatos a inhibidores de MMP1 y MMP12 a partir de compuestos de propóleos que pueden mejorar la cicatrización de heridas. Se espera que las pruebas reunidas en este estudio aporten nueva información crucial para explorar nuevos medicamentos para la cicatrización de heridas.

Palabras Clave: cicatrización de heridas; metaloproteinasas de matriz; propóleo; simulación de acoplamiento molecular; simulación de dinámica molecular.

 

https://jppres.com/jppres/pdf/vol12/jppres23.1719_12.2.264.pdf

Citation Format: Arda GA, Syaifie PH, Ramadhan D, Jauhar MM, Nugroho DW, Kaswati NMN, Noviyanto A, Andrianto D, Rochman NT, Safithri M, Mardliyati E (2024) Activity of propolis compounds as potential MMP1 and MMP2 inhibitors by in silico studies in wound healing application. J Pharm Pharmacogn Res 12(2): 264–285. https://doi.org/10.56499/jppres23.1719_12.2.264

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