Ligand-Based Drug Design of Genipin Derivatives with Cytotoxic Activity against HeLa Cell Line: A Structural and Theoretical Study

Author:

López-López Diana1ORCID,Razo-Hernández Rodrigo Said2ORCID,Millán-Pacheco César1ORCID,Leyva-Peralta Mario Alberto3,Peña-Morán Omar Aristeo4ORCID,Sánchez-Carranza Jessica Nayelli1ORCID,Rodríguez-López Verónica1ORCID

Affiliation:

1. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Mexico

2. Laboratorio de Quimioinformática y Diseño de Fármacos, Centro de Investigación en Dinámica Celular, Instituto de investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Mexico

3. Departamento de Ciencias Químico Biológicas y Agropecuarias, Universidad de Sonora, H. Caborca, Sonora 83621, Mexico

4. Departamento de Ciencias Farmacéuticas, División de Ciencias de la Salud, Universidad Autónoma del Estado de Quintana Roo, Chetumal 77019, 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.

Funder

CONAHCyT

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

Reference62 articles.

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2. (2023, July 10). GLOBOCAN-Global Cancer Observatory. Available online: https://gco.iarc.fr/.

3. Human papillomavirus and cervical cancer;Okunade;J. Obstet. Gynaecol.,2020

4. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics;Anand;Genes Dis.,2022

5. Neoadjuvant chemotherapy for locally advanced stage (IB2-IIA2-IIB) cervical carcinoma: Experience of a tertiary center and comprehensive review of the literature;Dur;Turk. J. Obstet. Gynecol.,2021

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