Annonaceous acetogenins as promising DNA methylation inhibitors to prevent and treat leukemogenesis – an in silico approach

Abstract

Leukemia is a haematological malignancy affecting blood and bone marrow, ranking 10^th among the other common cancers. DNA methylation is an epigenetic dysregulation that plays a critical role in leukemogenesis. DNA methyltransferases (DNMTs) such as DNMT1, DNMT3A and DNMT3B are the key enzymes catalysing DNA methylation. Inhibition of DNMT1 with secondary metabolites from medicinal plants helps reverse DNA methylation. The present study focuses on inhibiting DNMT1 protein (PDB ID: 3PTA) with annonaceous acetogenins through in-silico studies. The docking and molecular dynamic (MD) simulation study was carried out using Schrödinger Maestro and Desmond, respectively. These compounds’ drug likeliness, ADMET properties and bioactivity scores were analysed. About 76 different acetogenins were chosen for this study, among which 17 showed the highest binding energy in the range of −8.312 to −10.266 kcal/mol. The compounds with the highest negative binding energy were found to be annohexocin (-10.266 kcal/mol), isoannonacinone (-10.209 kcal/mol) and annonacin (-9.839 kcal/mol). MD simulation results reveal that annonacin remains stable throughout the simulation time of 100 ns and also binds to the catalytic domain of DNMT1 protein. From the above results, it can be concluded that annonacin has the potential to inhibit the DNA methylation process and prevent leukemogenesis.

Communicated by Ramaswamy H. Sarma

Keywords:

• Leukemia
• DNMT1
• annonaceous acetogenin
• molecular docking
• molecular dynamic simulation

Acknowledgments

The authors extend their appreciation to the Centre for Machine Learning and Intelligence (CMLI) laboratory in Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu, India – 641 043 for providing lab facility to carry out this research work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors sincerely thank the DST INSPIRE Fellowship (IF220035), Department of Science and Technology, Ministry of Science and Technology, Government of India, for funding this research.