Insights on inhibition of Plasmodium falciparum plasmepsin I by novel epoxyazadiradione derivatives – molecular docking and comparative molecular field analysis

Abstract

In the present study, we have explored the anti-malarial potential of epoxyazadiradione, the natural entity extracted from the neem seed oil and its chemical derivatives, against Plasmodium falciparum. The Surflex dock analysis of 41 compounds against an indispensable target, plasmepsin I (PM-I) revealed that around 70% of the compounds are found to have good binding capacity with the consensus score (C-score) of 5 to 4 with few hydrogen bonds. To elucidate the major structural requirements, vital for binding with the plasmepsin enzyme and to develop the predictive models, three-dimentional quantitative structural activity relationship (3D-QSAR) – comparative molecular field analysis (CoMFA) was carried out using Sybyl X.0. Robust and predictive models were obtained with cross-validated correlation coefficient (q²) value of 0.967 and the non-cross-validated correlation coefficient (r²) value of 0.825, which were validated by an external test set with the predictive correlation coefficient r²_(pred) values of 0.773. Three zones were identified for substitution with bulky groups and one zone for substitution with non-bulky groups. Three positions favouring the electronegative group substitution and one for the electropositive group substitution were identified. The physicochemical properties of ligands with the highest C-score were studied.

Communicated by Ramaswamy H. Sarma

Keywords:

• Azadirachta indica
• epoxyazadiradione
• CoMFA
• molecular docking
• P. falciparum

Acknowledgements

The authors would also like to thank the management of VIT for providing the necessary facilities to carry out this research project. 

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

SR and AA gratefully acknowledge the Indian Council of Medical Research (ICMR) and Government of India Agency for the research Grant (IRIS ID: 2014-0099). MT and KM heartfully thank the ICMR, for the grant of research associateship (IRIS ID: 2017-10050) and senior research fellowship (IRIS ID: 2015-25750), respectively.