Ligand-Based Drug Design of Genipin Derivatives with Cytotoxic Activity against HeLa Cell Line: A Structural and
Diana López-López1, Rodrigo Said Razo-Hernández2, César Millán-Pacheco1
1Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Mexico.
Abstract:
Cervical cancer is a malignant neoplastic disease, mainly associated to HPV infection, with high mortality rates. Among natural products, iridoids have shown different biological activities, including cytotoxic and antitumor effects, in different cancer cell types. Geniposide and its aglycone Genipin have been assessed against different types of cancer. In this work, both iridoids were evaluated against HeLa and three different cervical cancer cell lines. Furthermore, we performed a SAR analysis incorporating 13 iridoids with a high structural similarity to Geniposide and Genipin, also tested in the HeLa cell line and at the same treatment time. Derived from this analysis, we found that the dipole moment (magnitude and direction) is key for their cytotoxic activity in the HeLa cell line. Then, we proceeded to the ligand-based design of new Genipin derivatives through a QSAR model (R2 = 87.95 and Q2 = 62.33) that incorporates different quantum mechanic molecular descriptor types (ρ, ΔPSA, ∆Polarizability2, and logS). Derived from the ligand-based design, we observed that the presence of an aldehyde or a hydroxymethyl in C4, hydroxyls in C1, C6, and C8, and the lack of the double bond in C7-C8 increased the predicted biological activity of the iridoids. Finally, ten simple iridoids (D9, D107, D35, D36, D55, D56, D58, D60, D61, and D62) are proposed as potential cytotoxic agents against the HeLa cell line based on their predicted IC50 value and electrostatic features.
Insights
This study explores iridoids as potential cervical cancer treatments. Key findings show specific molecular features enhance cytotoxic activity against HeLa cells, leading to the proposal of ten novel iridoid compounds.
Area of Science:
- Natural Product Chemistry
- Medicinal Chemistry
- Computational Chemistry
Background:
- Cervical cancer, a significant neoplastic disease linked to HPV, presents high mortality rates.
- Iridoids, natural products, exhibit promising cytotoxic and antitumor activities against various cancer types.
- Geniposide and Genipin are iridoids with known anticancer potential, necessitating further investigation.
Purpose of the Study:
- To evaluate the cytotoxic effects of Geniposide and Genipin on cervical cancer cell lines, including HeLa.
- To conduct a Structure-Activity Relationship (SAR) analysis of 13 iridoids against HeLa cells.
- To design novel Genipin derivatives using Quantitative Structure-Activity Relationship (QSAR) modeling for enhanced cervical cancer therapy.
Main Methods:
- Cytotoxicity assays were performed on HeLa and three other cervical cancer cell lines.
- SAR analysis involved 13 structurally similar iridoids tested on HeLa cells.
- QSAR modeling utilized quantum mechanical descriptors (ρ, ΔPSA, ∆Polarizability2, logS) for ligand-based design.
Main Results:
- Dipole moment (magnitude and direction) was identified as crucial for cytotoxic activity in HeLa cells.
- QSAR model (R² = 87.95, Q² = 62.33) predicted enhanced activity with specific structural modifications.
- Presence of aldehyde/hydroxymethyl at C4, hydroxyls at C1, C6, C8, and absence of C7-C8 double bond increased predicted iridoid activity.
Conclusions:
- Molecular features like dipole moment are critical for iridoid cytotoxic activity against cervical cancer.
- Ligand-based QSAR design successfully identified key structural elements for enhanced biological activity.
- Ten novel iridoids (D9, D107, D35, D36, D55, D56, D58, D60, D61, D62) show potential as cytotoxic agents against HeLa cells.
