Potential of pyrroquinazoline alkaloids from Adhatoda vasica Nees. as inhibitors of 5-LOX – a computational and an in-vitro study

Abstract

Inflammation plays a major role in the onset and progression of many diseases related to the respiratory system. Cysteinyl leukotrienes, the products of 5-LOX are a potent bronchoconstrictor. Vasicine, vasicinone and deoxyvasicine are the pyrroquinazoline alkaloids of Adhatoda vasica that are well known for their bronchodilatory activity. The current investigation evaluates the 5-LOX inhibitory potential of these alkaloids. Molecular docking results indicated that these alkaloids have similar binding energy as that of Zileuton, a commercial drug. Analysis of the molecular dynamics simulations, the binding free energy derived from MM-PBSA and interaction entropy indicated that vasicinone (-8.33 kcal/mol) exhibited a binding free energy comparable to that of Zileuton (-8.52 kcal/mol). The in-vitro results indicate the potential of vasicinone as a competitive inhibitor, while the in-silico results highlighted the potential of vasicine and deoxyvasicine as allosteric inhibitors. A possible mechanism behind the activity exhibited by the plant was also determined, which emphasized the potential of these alkaloids as leads for the design of novel 5-LOX inhibitors

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• 5-LOX
• vasicine
• vasicinone
• deoxyvasicine
• Zileuton
• anti-inflammatory

Acknowledgements

The authors dedicate this work as an offering to Bhagawan Sri Sathya Sai Baba. The authors acknowledge DMACS, Sri Sathya Sai Institute of Higher Learning, for extending the support in installing and running AMBER MD simulations, the gift of a pT3 5-LOX plasmid from Prof. Olof Rådmark, Karolinska Institute, Stockholm, Sweden and UGC-SAP-DRS, UGC-BSR and DBT-BIF for financial support and fellowship. Thanks also to V Srivarun, K K Sai Anand, M Sai Kiran, Dr. C Sai Manohar, Dr K N Naresh and S Bharath Reddy for their support in carrying out this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

PG performed the experiments, drafted the manuscript with the guidance provided by MD and BR. SS standardized the in-vitro enzyme inhibition assay protocol and helped in analysing the same.

Additional information

Funding

This work was supported by Department of Biotechnology, Ministry of Science and Technology (BT/BI/25/063/2012 (BIF-SSSIHL)); University Grants Commission (10.13039/100015747 & F. 7-164/2007(BSR)).