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. 2024 Feb 27:17:33-46.
doi: 10.2147/AABC.S452281. eCollection 2024.

Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study

Hesti Lina Wiraswati  1   2 , Muhammad Hasan Bashari  1   2 , Nayla Majeda Alfarafisa  1   2 , Ilma Fauziah Ma'ruf  3 , Eti Nurwening Sholikhah  4 , Tutik Dwi Wahyuningsih  5 , Pamungkas Bagus Satriyo  4 , Mustofa Mustofa  4 , Denny Satria  6 , Ema Damayanti  7
Affiliations

Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study

Hesti Lina Wiraswati et al. Adv Appl Bioinform Chem. .

Abstract

Background: Multidrug resistance in various cancer types is a major obstacle in cancer treatment. The concept of a single drug molecular target often causes treatment failure due to the complexity of the cellular processes. Therefore, combination chemotherapy, in which two or more anticancer drugs are co-administered, can overcome this problem because it potentially have synergistic efficacy besides reducing resistance, and drug doses. Previously, we reported that pyrazoline B had promising anticancer activity in both in silico and in vitro studies. To increase the efficacy of this drug, co-administration with established anticancer drugs such as doxorubicin and paclitaxel is necessary.

Materials and methods: In this study, we used an in silico approach to predict the synergistic effect of pyrazoline B with paclitaxel or doxorubicin using various computational frameworks and compared the results with those of an established study on the combination of doxorubicin-cyclophosphamide and paclitaxel-ascorbic acid.

Results and discussion: Drug interaction analysis showed the combination was safe with no contraindications or side effects. Furthermore, molecular docking studies revealed that doxorubicin-pyrazoline B and doxorubicin-cyclophosphamide may synergistically inhibit cancer cell proliferation by inhibiting the binding of topoisomerase I to the DNA chain. Moreover, the combination of pyrazoline B-paclitaxel may has synergistic activity to cause apoptosis by inhibiting Bcl2 binding to the Bax fragment or inhibiting cell division by inhibiting α-β tubulin disintegration. Paclitaxel-ascorbic acid had a synergistic effect on the inhibition of α-β tubulin disintegration.

Conclusion: The results show that this combination is promising for further in vitro and in vivo studies.

Keywords: doxorubicin; in silico study; paclitaxel; pyrazoline B; synergistic effect.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Visualization of advantages of combination chemotherapy.
Figure 2
Figure 2
Protein-ligand docking and macromolecular docking of topoisomerase I. (A) The binding of topoisomerase I and pyrazoline B (green) or doxorubicin (red). (B) The binding of topoisomerase I and cyclophosphamide (cyan) or doxorubicin (red). (C) Pyrazoline B-topoisomerase I interaction. (D) Cyclophosphamide-topoisomerase I interaction. (E) Doxorubicin-topoisomerase I interaction. (F) Topoisomerase I without ligand. (G) Topoisomerase I-doxorubicin. (H) Topoisomerase I-pyrazoline B. (I) Topoisomerase I-Doxorubicin-pyrazoline B. (J) Topoisomerase I cyclophosphamide. (K) Topoisomerase I-doxorubicin-cyclophosphamide.
Figure 3
Figure 3
Docking of topoisomerase II and ligands. (A) The binding of topoisomerase II and pyrazoline B (green) or doxorubicin (red). (B) The binding of topoisomerase II and cyclophosphamide (cyan) or doxorubicin (red). (C) Pyrazoline-topoisomerase II interaction. (D) Cyclophosphamide-topoisomerase II interaction. (E) Doxorubicin-topoisomerase II interaction.
Figure 4
Figure 4
Protein-ligand docking and macromolecular docking of α tubulin. (A) Pyrazoline B (green) and Paclitaxel (Orange) binding to α-β tubulin. (B) Ascorbic acid (blue) and Paclitaxel (Orange) binding to α-β tubulin. (C) α-β tubulin-pyrazoline B. (D) α-β tubulin-ascorbic acid. (E) α- β tubulin-paclitaxel. (F) α-tubulin without ligand. (G) α tubulin-Paclitaxel. (H) α tubulin-pyrazoline B. (I) α tubulin-Paclitaxel-pyrazoline B. (J) α tubulin-ascorbic acid. (K) α tubulin-Paclitaxel-ascorbic acid.
Figure 5
Figure 5
Protein-ligand docking and macromolecular docking of Bcl2. (A) Pyrazoline B (green) and Paclitaxel (Orange) binding to Bcl2. (B) Ascorbic acid (blue) and Paclitaxel (Orange) binding to Bcl2. (C) Pyrazoline B interaction with residues on Bcl2. (D) Ascorbic acid interaction with residues on Bcl2. (E) Paclitaxel interaction with residues on Bcl2. (F) Bcl2 without ligand. (G) Bcl2-Paclitaxel. (H) Bcl2-pyrazoline B. (I) Bcl2-Paclitaxel-pyrazoline B. (J) Bcl2-ascorbic acid. (K) Bcl2-Paclitaxel-ascorbic acid.
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