A Computational Approach towards the Understanding of Plasmodium falciparum Multidrug Resistance Protein 1

Abstract

The emergence of drug resistance in Plasmodium falciparum tremendously affected the chemotherapy worldwide while the intense distribution of chloroquine-resistant strains in most of the endemic areas added more complications in the treatment of malaria. The situation has even worsened by the lack of molecular mechanism to understand the resistance conferred by Plasmodia species. Recent studies have suggested the association of antimalarial resistance with P. falciparum multidrug resistance protein 1 (PfMDR1), an ATP-binding cassette (ABC) transporter and a homologue of human P-glycoprotein 1 (P-gp1). The present study deals about the development of PfMDR1 computational model and the model of substrate transport across PfMDR1 with insights derived from conformations relative to inward- and outward-facing topologies that switch on/off the transportation system. Comparison of ATP docked positions and its structural motif binding properties were found to be similar among other ATPases, and thereby contributes to NBD domains dimerization, a unique structural agreement noticed in Mus musculus Pgp and Escherichia coli MDR transporter homolog (MsbA). The interaction of leading antimalarials and phytochemicals within the active pocket of both wild-type and mutant-type PfMDR1 demonstrated the mode of binding and provided insights of less binding affinity thereby contributing to parasite's resistance mechanism.

Evolution of the Plasmodium vivax multidrug resistance 1 gene in the Greater Mekong Subregion during malaria elimination

“…1). The predicted domains in PvMDR1 show high sequence homology to the corresponding PfMDR1 functional domains [54]. For the 71 mutations reported in this study, 38 are predicted to be deleterious by at least one of the prediction programs (Additional file 2: Table S2), whereas 19 are predicted to be detrimental according to both Provean and SIFT analysis (Additional file 3: Table S3).…”

“…All these mutations can potentially affect the structural integrity of the protein by altering the charges, hydrophobicity, or size of the amino acids. In addition, the residues corresponding to L470, L610, and D611 in PfMDR1 are predicted to be involved in NDB dimerization [54], and mutations at these positions may hinder dimerization of the protein. Insights into the ATP-binding pockets can help decipher if any of these residues are involved in direct binding to ATP or some antimalarial drugs, allowing the determination of their potential role in transport and resistance.…”

Monitoring PfMDR1 transport in Plasmodium falciparum

“…Computational models of PfMDR1 describe a substrate-binding pocket that includes the amino acid residues 1034 and 1042 [ 4 , 13 ]. The binding of several anti-malarial drugs was investigated using docking simulations within the PfMDR1 substrate-binding pocket.…”

“…The binding of several anti-malarial drugs was investigated using docking simulations within the PfMDR1 substrate-binding pocket. Among the tested drugs, MQ was the only candidate whose ability to form an H-bond with residue 1042 was completely abolished through the N1042D substitution [ 13 ].…”

200 Structural insights into the theoretical model ofPlasmodium falciparummulti drug resistance 1 protein (PfMDR1) and its interaction with phytochemicals as efficacious antimalarial drugs: anin silicoandin vitroapproach

“…In our earlier work, we developed PfMDR1 computational model and studied the model of substrate transport across PfMDR1 with insights derived from conformations relative to inward-and outward-facing topologies that switch on/off the transportation system (Patel et al, 2013).…”