Docking and molecular dynamics studies of potential new leads against DBL3x derived from chondroitin sulfate A (CSA): a new approach for the treatment of malaria

Abstract

In this work the DBL3x domain of the erythrocyte membrane protein from Plasmodium Falciparum (PfEMP1), was revisited as a potential molecular target for the development of new drugs against malaria. This protein interacts with chondroitin sulfate A (CSA), a glycosaminoglycan present in the substance fundamental for connective tissues of vertebrates and is implicated in malaria complications in pregnant women. We performed molecular docking and molecular dynamic studies of DBL3x complexed with CSA and five analogues, where the sulfate group was replaced by phosphate, in order to evaluate if the better electrostatic interactions provided by phosphate groups could afford better binders capable of preventing the binding of CSA to DBL3x. Results suggest that all proposed compounds have high affinity towards DBL3x and could bind better to the DBL3x domain of PfEMP1 than CSA, qualifying as potential inhibitors of this protein and, therefore, new potential leads for the drug design against malaria.

Communicated by Ramaswamy H. Sarma

Keywords:

• Chondrointin derivatives
• malaria
• molecular docking
• molecular dynamics

Acknowledgements

The authors wish to thank the financial support of the Brazilian agencies: CNPq (grant no 308225/2018-0), FAPERJ (grant no E-02/202.961/2017), FAPESP (grants no 2018/03910-1 and 2020/06536-3), FAEPEX (grant no 2466/20), FES-PRPPG (grant no 10/2019), FAPES (grant no 03/2020-2020-WMT5F), and CENAPAD-SP, CENAPAD-UFC and CESUP for computational support. This work was also supported by the University of Hradec Krélové.

Disclosure statement

No potential conflict of interest was reported by the authors.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.