3D QSAR pharmacophore based lead identification of G9a lysine methyltransferase towards epigenetic therapeutics

Abstract

The G9a, Lysine Methyltransferase that methylates the histone 3 lysine 9 (H3K9) of the nucleosome, is an excellent epigenetic target having no clinically passed inhibitor currently owing to adverse in vivo ADMET toxicities. In this work, we have carried out detailed computational investigations to find novel and safer lead against the target using advanced 3 D QSAR pharmacophore screening of databases containing more than 400000 entrees of natural compounds. The screening was conducted at different levels at increasing stringencies by employing pharmacophore mapping, druglikenesses and interaction profiles of the selected to identify potential hit compounds. The potential hits were further screened by advanced flexible docking, ADME and toxicity analysis to eight hit compounds. Based on the comparative analysis of the hits with the reference inhibitor, we identified one lead inhibitor against the G9a, having better binding efficacy and a safer ADMET profile than the reference inhibitor. Finally, the results were further verified using robust molecular dynamics simulation and MM-GBSA binding energy calculation. The natural compounds are generally considered benign due to their long human uses and this is the first attempt of in silico screening of a large natural compound library against G9a to our best knowledge. Therefore, the finding of this study may add value towards the development of epigenetic therapeutics against the G9a.

Communicated by Ramaswamy H. Sarma

Keywords:

• ADMET
• Cancer
• Chromatin
• Histone PTM
• MD Simulation
• Molecular docking
• QSAR

Acknowledgement

DRB wants to express his gratitude to the National Institute of Technology Durgapur (NITDGP) for the platform and for providing the fund through RIG grant and institute fund for the purchase the license of BIOVIA Discovery Studio academic research suite. DRB also wants to thank Department of Chemistry (NITDGP) for the space allocated for research and to the FIST grant for the procurement of the computer server nodes. DRB also acknowledge the support of Dr. Subhas Ghosal for all the necessary supports. AJ wants to thank the National Institute of Technology Durgapur (NITDGP) for the institute fellowship.

Disclosure statement

The authors have no potential conflicts of interest (financial or non-financial) to disclose. No study-specific approval or consent by the appropriate ethics committee was required for this study.

Funding

The study was not funded by any external grant/fund.

Author’s contribution

AJ carried out the experiments and helped in preparing the manuscript. RN and SS helped in MD simulation. DRB conceived the idea, mentored the research and wrote the manuscript.

Data availability statement

All data generated or analyzed during this study are included in this published article [and its supplementary information files].