ePrints@IIScePrints@IISc Home | About | Browse | Latest Additions | Advanced Search | Contact | Help

In silico modeling of Plasmodium falciparum chloroquine resistance transporter protein and biochemical studies suggest its key contribution to chloroquine resistance

Antony, Hiasindh Ashmi and Topno, Nishith Saurav and Gummadi, Sathyanarayana N and Sankar, Devanarayanan Siva and Krishna, Ramadas and Parija, Subhash Chandra (2019) In silico modeling of Plasmodium falciparum chloroquine resistance transporter protein and biochemical studies suggest its key contribution to chloroquine resistance. In: ACTA TROPICA, 189 . pp. 84-93.

[img] PDF
Act_Tro_189-84_2019.pdf - Published Version
Restricted to Registered users only

Download (2MB) | Request a copy
Official URL: http://dx.doi.org/10.1016/j.actatropica.2018.10.00...

Abstract

Chloroquine (CQ) has been used for decades as the primary chemotherapeutic drug for the treatment of malaria. The emergence of drug resistance in Plasmodium falciparum has been considered to be because of the excessive use of antimalarial drugs worldwide. Moreover, the intense distribution and prevalence of chloroquine-resistant strains in endemic regions has aided the incidence of more complications to malaria treatment and control. Due to the lack of literature that portrays evident molecular mechanisms of drug resistance, it has been difficult to understand the drug resistance conferred by Plasmodium species. Intensive research on CQ drug resistance has identified the association of P. falciparum chloroquine resistance transporter protein (PfCRT), which belongs to the drug/metabolite transporter and EamA-like superfamily. Additionally, it has shown that K76 T mutation in PfCRT protein has mainly attributed to CQ resistance than other mutations. This study deals with the development of an in silica model of the PfCRT protein and its interaction with the CQ ligand molecule as well as the biochemical and biophysical characterization of the transmembrane domain 1 (TMD 1) peptide of the PfCRT protein. The physiochemical analysis of the PfCRT protein identified basic differences between the wild and mutant forms of the protein, as well as identifying the high hydrophobic nature of the mutant-type protein. The tertiary structure of the PfCRT protein was predicted and interaction with CQ revealed different active pocket binding regions in both the wild and mutant form of PfCRT proteins. The CQ2 molecule interacts with TMD 10 of the wild-type PfCRT protein, whereas it interacts with TMD 1 of the mutant-type protein. Studies on the TMD 1 peptide revealed the insertion of the peptide in the micelles adopting stable alpha-helical structure. Binding studies with the CQ molecule detected high binding affinity toward the mutant-type TMD 1 peptide rather than the wild-type, thus confirming that the TMD 1 peptide is involved in substrate selectivity. Our findings help to characterize the structure of the PfCRT protein and the role played by the TMD 1 region in CQ resistance using in silica and biochemical approaches. Molecular docking and ligand binding studies confirm that TMD 1 is involved in substrate selectivity and aids in CQ efflux, thereby contributing to the parasites CQ drug resistance mechanism.

Item Type: Journal Article
Publication: ACTA TROPICA
Publisher: ELSEVIER SCIENCE BV
Additional Information: copy right for this article belong to ELSEVIER SCIENCE BV
Keywords: Chloroquine; P. falciparurn chloroquine resistance transporter protein (PfCRT); Transmembrane domain (TMD); Tertiary structure prediction; Molecular docking
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 06 Dec 2018 10:54
Last Modified: 06 Dec 2018 10:54
URI: http://eprints.iisc.ac.in/id/eprint/61204

Actions (login required)

View Item View Item