In silico modeling of Plasmodium falciparum chloroquine resistance transporter protein and biochemical studies suggest its key contribution to chloroquine resistance
| Autor: | Ramadas Krishna, Sathyanarayana N. Gummadi, Subhash Chandra Parija, Nishith Saurav Topno, Devanarayanan Siva Sankar, Hiasindh Ashmi Antony |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Veterinary (miscellaneous) 030231 tropical medicine Drug Resistance Protozoan Proteins Plasma protein binding Drug resistance 03 medical and health sciences Antimalarials 0302 clinical medicine Chloroquine parasitic diseases medicine Animals Humans Computer Simulation Malaria Falciparum biology Chemistry Membrane transport protein Membrane Transport Proteins Plasmodium falciparum 030108 mycology & parasitology biology.organism_classification Protein tertiary structure Transport protein Transmembrane domain Infectious Diseases Biochemistry Insect Science biology.protein Parasitology medicine.drug |
| Zdroj: | Acta tropica. 189 |
| ISSN: | 1873-6254 |
| Popis: | 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 silico 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 silico 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 parasite's CQ drug resistance mechanism. |
| Databáze: | OpenAIRE |
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