Computational investigation of four isoquinoline alkaloids against polycystic ovarian syndrome

Area of Science:

• Pharmacology and Phytochemistry
• Molecular Biology
• Endocrinology

Background:

• Polycystic Ovarian Syndrome (PCOS) is characterized by hyperandrogenism, insulin resistance, and estrogen dominance.
• These hormonal imbalances disrupt ovarian function, leading to impaired folliculogenesis and excess androgen production.
• Current treatments for PCOS often have limitations, necessitating the search for novel therapeutic agents.

Purpose of the Study:

• To identify potent bioactive antagonistic ligands from isoquinoline alkaloids in Tinospora cordifolia.
• To evaluate the inhibitory potential of these compounds against key targets in PCOS pathogenesis, including androgen, estrogen, and insulin receptors, as well as steroidogenic enzymes.
• To explore the therapeutic potential of these natural compounds for PCOS management.

Main Methods:

• Virtual screening using molecular docking (Autodock Vina 4.2.6) against human androgen receptor (1E3G), insulin receptor (3EKK), estrogen receptor beta (1U3S), and P450 17A1 (6WR0).
• Ligand flexibility was incorporated in docking studies.
• ADMET prediction using swissADME and toxicological assessments were performed.
• Binding affinity and molecular dynamics simulations were conducted using Schrodinger to assess binding stability.

Main Results:

• Berberine (BBR) and Palmatine (PAL) exhibited the most significant docking scores against androgen receptors, with BBR showing a score of -8.23 and PAL -6.71.
• Both BBR and PAL were identified as tight binders at the active site of the human androgen receptor (1E3G).
• Molecular dynamics simulations confirmed the stable binding of BBR and PAL within the active site residues, indicating their potential as effective inhibitors.

Conclusions:

• Isoquinoline alkaloids, specifically Berberine (BBR) and Palmatine (PAL) from Tinospora cordifolia, demonstrate significant potential as therapeutic agents for PCOS.
• These compounds act as potent inhibitors of androgen receptors, addressing a key factor in PCOS.
• The findings support the development of BBR and PAL as novel drug candidates for PCOS treatment, based on virtual screening and molecular dynamics evaluations.