Abstract
A new dimeric sesquiterpene named disesquicin (compound 1) was isolated from Inula racemosa roots by normal-phase MPLC (Medium Pressure Liquid Chromatography), and its structure was established by using extensive spectral analysis. Compound 1, when tested on different human cancer cell lines, showed marked cytotoxic activity (IC50 (µg/mL): 5.99 (MDA-MB), 9.10 (HeLa), and 12.47 (A549)). Docking study revealed that it binds at the catalytic domain of PLK-1 and interacts with catalytic site residues Leu59, Gly60, Lys61, Gly62, Cys67, Ala80, Lys82, Leu130, Arg136, Ser137, Leu139, Glu140, Lys178, Gly180, Asn181, Phe183, and Asp194. The binding of compound 1 to PLK-1 is spontaneous in nature as evident by a free energy of—8.930 kcal mol−1, corresponding to a binding affinity of 3.54 × 106 M−1. Results showed that compound 1 exhibited cytotoxic potential that was further confirmed by in vivo investigations.
Highlights
Cancer is one of the most deplorable diseases and a prevalent cause of worldwide death.According to the World Health Organization (WHO), nearly 9.5 million people died in 2018 due to cancer, and the main reason for death is the reappearance of treatment-resistant cancer cells in the infected area [1]
We report for the first time the isolation of a new dimeric sesquiterpene (Compound 1) from the roots of I. racemosa
Compound 1 was explored for its cytotoxic potential against different cancer cell lines such as HeLa, MDAMB231, and A549 by MTT assay, and the in vitro results were validated by molecular docking and molecular dynamics simulation
Summary
Cancer is one of the most deplorable diseases and a prevalent cause of worldwide death. An analysis of the PLK-1 structure revealed two major druggable sites, namely (i) kinase domain harboring ATP binding site and (ii) polo-box domain. Previous studies have established that the ATP binding site in the kinase domain is the most preferred site for drug-designing. 50–60% of presently available anticancer drugs in the market (like taxol, vincristine, vinblastine etc.) are derived from natural product scaffold [6]. We report for the first time the isolation of a new dimeric sesquiterpene (Compound 1) from the roots of I. racemosa. Compound 1 was explored for its cytotoxic potential against different cancer cell lines such as HeLa (cervical), MDAMB231 (breast), and A549 (lung) by MTT assay, and the in vitro results were validated by molecular docking and molecular dynamics simulation
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