Tanshinone-I for the treatment of uterine fibroids: Molecular docking, simulation, and density functional theory investigations

Abhishek Tiwari; Varsha Tiwari; Ajay Sharma; Deependra Singh; Manju Singh Rawat; Tarun Virmani; Reshu Virmani; Girish Kumar; Manish Kumar; Abdulsalam Alhalmi; Omar M Noman; Ramzi A Mothana; Mohammad Alali

doi:10.1016/j.jsps.2023.05.002

Tanshinone-I for the treatment of uterine fibroids: Molecular docking, simulation, and density functional theory investigations

Saudi Pharm J. 2023 Jun;31(6):1061-1076. doi: 10.1016/j.jsps.2023.05.002. Epub 2023 May 8.

Authors

Affiliations

¹ Department of Pharmacy, Pharmacy Academy, IFTM University, Lodhipur-Rajpur, Moradabad 244102, India.
² Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi 110017, India.
³ University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh, India.
⁴ School of Pharmaceutical Sciences, MVN University, Palwal, Haryana 121105, India.
⁵ School of Pharmaceutical Sciences, CT University, Ludhiana- 142024 Punjab, India.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy, Aden University, Aden, Yemen.
⁷ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁸ Institute of Pharmacy, Clinical Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany.

Abstract

Uterine fibroids (UF), most prevalent gynecological disorder, require surgery when symptomatic. It is estimated that between 25 and 35 percent of women wait until the symptoms have worsened like extended heavy menstrual bleeding and severe pelvic pain. These UF may be reduced in size through various methods such as medical or surgical intervention. Progesterone (prog) is a crucial hormone that restores the endometrium and controls uterine function. In the current study, 28 plant-based molecules are identified from previous literature and docked onto the prog receptors with 1E3K and 2OVH. Tanshinone-I has shown the best docking score against both proteins. The synthetic prog inhibitor Norethindrone Acetate is used as a standard to evaluate the docking outcomes. The best compound, tanshinone-I, was analyzed using molecular modeling and DFT. The RMSD for the 1E3K protein-ligand complex ranged from 0.10 to 0.42 Å, with an average of 0.21 Å and a standard deviation (SD) of 0.06, while the RMSD for the 2OVH protein-ligand complex ranged from 0.08 to 0.42 Å, with an average of 0.20 Å and a SD of 0.06 showing stable interaction. In principal component analysis, the observed eigen values of HPR-Tanshinone-I fluctuate between -1.11 to 1.48 and -1.07 to 1.25 for PC1 and PC2, respectively (1E3K), and the prog-tanshinone-I complex shows eigen values of -38.88 to -31.32 and -31.32 to 35.87 for PC1 and PC2, respectively (2OVH), which shows Tanshinone-I forms a stable protein-ligand complex with 1E3K in comparison to 2OVH. The Free Energy Landscape (FEL) analysis shows the Gibbs free energy in the range of 0 to 8 kJ/mol for Tanshinone-I with 1E3K and 0 to 14 kJ/mol for Tanshinone-I with the 2OVH complex. The DFT calculation reveals ΔE value of 2.8070 eV shows tanshinone-I as a stable compound. 1E3K modulates the prog pathway, it may have either an agonistic or antagonistic effect on hPRs. Tanshinone-I can cause ROS, apoptosis, autophagy (p62 accumulation), up-regulation of inositol requiring protein-1, enhancer-binding protein homologous protein, p-c-Jun N-terminal kinase (p-JNK), and suppression of MMPs. Bcl-2 expression can change LC3I to LC3II and cause apoptosis through Beclin-1 expression.

Keywords: Docking; Molecular modelling; Progesterone blocker; Tanshinone-I; Uterine fibroids.