Exploration of cell cycle regulation and modulation of the DNA methylation mechanism of pelargonidin: Insights from the molecular modeling approach

Natesan Karthi; Arumugasamy Karthiga; Thangaraj Kalaiyarasu; Antony Stalin; Vaiyapuri Manju; Sanjeev Kumar Singh; Ravi Cyril; Sang-Myeong Lee

doi:10.1016/j.compbiolchem.2017.08.002

Exploration of cell cycle regulation and modulation of the DNA methylation mechanism of pelargonidin: Insights from the molecular modeling approach

Comput Biol Chem. 2017 Oct:70:175-185. doi: 10.1016/j.compbiolchem.2017.08.002. Epub 2017 Aug 8.

Authors

Natesan Karthi¹, Arumugasamy Karthiga², Thangaraj Kalaiyarasu³, Antony Stalin⁴, Vaiyapuri Manju⁵, Sanjeev Kumar Singh⁶, Ravi Cyril², Sang-Myeong Lee⁷

Affiliations

¹ Department of Biochemistry, Periyar University, Salem 636011, Tamilnadu, India; Division of Biotechnology, Advanced Institute of Environment and Bioscience, Safety, Environment and Life Science Institute, College of Environmental and Bioresource Sciences, Chonbuk National University, Iksan 54596, South Korea.
² Department of Zoology, Thiagarajar College, Madurai 625009, Tamilnadu, India.
³ Department of Biochemistry, Periyar University, Salem 636011, Tamilnadu, India.
⁴ Center for Advanced Studies (CAS) in Botany, University of Madras, Guindy Campus, Chennai - 600 025. India.
⁵ Department of Biochemistry, Periyar University, Salem 636011, Tamilnadu, India. Electronic address: manjucbll@gmail.com.
⁶ Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi 630 003, Tamil Nadu, India.
⁷ Division of Biotechnology, Advanced Institute of Environment and Bioscience, Safety, Environment and Life Science Institute, College of Environmental and Bioresource Sciences, Chonbuk National University, Iksan 54596, South Korea. Electronic address: leesangm@jbnu.ac.kr.

PMID: 28950208
DOI: 10.1016/j.compbiolchem.2017.08.002

Abstract

Pelargonidin is an anthocyanidin isolated from plant resources. It shows strong cytotoxicity toward various cancer cell lines, even though the carcinogenesis-modulating pathway of pelargonidin is not yet known. One of our previous reports showed that pelargonidin arrests the cell cycle and induces apoptosis in HT29 cells. Flowcytometry and immunoblot analysis confirmed that pelargonidin specifically inhibits the activation of CDK1 and blocks the G2-M transition of the cell cycle. In addition, DNA fragmentation was observed along with induction of cytochrome c release-mediated apoptosis. Hence, the aim of the present study was to investigate the molecular mechanism of pelargonidin's action on cell cycle regulators CDK1, CDK4, and CDK6 as well as the substrate-binding domain of DNMT1 and DNMT3A, which regulate the epigenetic signals related to DNA methylation. The results of docking analysis, binding free energy calculation, and molecular dynamics simulation correlated with the experimental results, and pelargonidin showed a specific interaction with CDK1. In this context, pelargonidin may also inhibit the recognition of DNA and catalytic binding by DNMT1 and DNMT3A. The HOMO-LUMO analysis mapped the functional groups of pelargonidin. Prediction of pharmacological descriptors suggested that pelargonidin can serve as a multitarget inhibitor for cancer treatment.

Keywords: Anthocyanidin; Cell cycle; DNA methylation; Docking; Molecular dynamics.

MeSH terms

Anthocyanins / chemistry
Anthocyanins / pharmacology*
CDC2 Protein Kinase / antagonists & inhibitors
CDC2 Protein Kinase / metabolism
Cell Cycle / drug effects*
DNA Methylation / drug effects*
Humans
Models, Molecular*
Quantum Theory
Thermodynamics

Substances

Anthocyanins
pelargonidin
CDC2 Protein Kinase
CDK1 protein, human