Deciphering the binding mechanism of an anti-cancer phytochemical plumbagin with calf thymus DNA using biophysical and in silico techniques

Abdul Rahaman; Farah Anjum; Aknita Kumari; Alaa Shafie; Mahafooj Alee; Omnia Badr; Shaheer Hasan Khan; Amal Adnan Ashour; Ali Hazazi; Sultan Arif; Xin-An Zeng

doi:10.3389/fchem.2023.1248458

Deciphering the binding mechanism of an anti-cancer phytochemical plumbagin with calf thymus DNA using biophysical and in silico techniques

Front Chem. 2023 Aug 29:11:1248458. doi: 10.3389/fchem.2023.1248458. eCollection 2023.

Authors

Abdul Rahaman^{1

2}, Farah Anjum³, Aknita Kumari⁴, Alaa Shafie³, Mahafooj Alee⁴, Omnia Badr⁵, Shaheer Hasan Khan⁶, Amal Adnan Ashour⁷, Ali Hazazi⁸, Sultan Arif⁹, Xin-An Zeng^{1

2

4

10}

Affiliations

¹ Guangdong Key Laboratory of Food Intelligent Manufacturing, Foshan University, Foshan, Guangdong, China.
² School of Food Science and Engineering, Foshan University, Foshan, China.
³ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
⁴ School of Food Science and Engineering, South China University of Technology, Guangzhou, China.
⁵ Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Qalyubia, Egypt.
⁶ Enzymology and Nanotechnology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
⁷ Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Faculty of Dentistry, Taif University, Taif, Saudi Arabia.
⁸ Department of Pathology and Laboratory Medicine, Security Forces Hospital Program, Riyadh, Saudi Arabia.
⁹ Department of Plastic Surgery and Burn Unit, Security Forces Hospital, Riyadh, Saudi Arabia.
¹⁰ Overseas Expertise Introduction Centre for Discipline Innovation of Food Nutrition and Human Health (111 Centre), Guangzhou, China.

Abstract

Plumbagin (PLM), a plant derivative, is well known for a wide range of therapeutic effects in humans including anti-cancer, anti-inflammatory, anti-oxidant, and anti-microbial. Cytotoxic and genotoxic potential of this phytochemical has been studied which demands further insight. DNA being a major target for several drugs was taken to study against PLM to understand its effects on the cellular system. UV-Vis spectroscopy has indicated the binding of PLM to ctDNA and dye displacement assays have confirmed the formation of PLM-ctDNA complex. The insignificant changes in circular dichroism spectra suggested that PLM is not affecting the structural makeup of the ctDNA, hence the binding could be peripheral and not intercalating. Further, the relative viscosity and minimal change in melting temperature upon the complex formation supported this finding and confirmed the groove binding of PLM. Molecular docking analysis and simulation studies also show PLM as a minor groove binder to DNA and provide details on the interaction dynamics of PLM-DNA complex. Docking followed by a 100 ns simulation reveals the negative Gibbs free energy change (∆G = -6.6 kcal mol^-1), and the formation of a stable complex. The PLM- DNA complex with stable dynamics was further supported by different parameters including RMSD, RMSF, SASA, Rg, and the energy profile of interaction. This study provides an insight into the cytotoxic and genotoxic mechanism of PLM which can be a crucial step forward to exploit its therapeutic potential against several diseases including cancer.

Keywords: Plumbagin; biophysical; cancer; circular dichroism; groove binder; molecular simulation.

Grants and funding

This work was supported by the S&T Project of Yangjiang (SDZX2020012), Guangdong Provincial Key Laboratory of Intelligent Food Manufacturing (2022B1212010015), the National Natural Science Foundation of China (32172348, 31972205), the Key Science and Technology projects of Xinjiang Uygur Autonomous Regions (2022A02002-4), and the S&T Project of China-Singapore International Joint Research Institute (201-A022005).