Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Structural Insights into the Theoretical Model of Plasmodium falciparum Multi Drug Resistance 1 protein (PfMDR1) and its Interaction with phytochemicals as efficacious antimalarial drugs: An in silico and in vitro approach
The failure of commonly used antimalarial agents in treating Chloroquine-resistant Plasmodium falciparum had complicated the management of malaria in most of the developing countries. Recent studies have shown a strong association between chloroquine-resistant strains and the molecular changes in Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) (Foote et al, 1990; van Es et al, 1994).
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).
The medicinal plants were selected on the basis of its traditional claims and degree of research work done so far as potent anti-plasmodial agents viz. Catharanthus roseus and Tylophora indica. In the present study, the molecular docking and dynamics trajectory of PfMDR1-phytochemicals complexes yielded an averaged structure with significant binding modes compared to PfMDR1 molecules. The interaction pattern of selected phytochemicals in PfMDR1 wild- and mutant-types showed the high ligand surface area as well as the electrostatic and hydrophobic contacts largely improved the binding affinity besides the contacts made with functional amino acids. The crucial role of interacting amino acids in substrate specificity was studied using molecular dynamic (MD) simulations which indicated the potential role of these amino acids in the translocation of molecules across the membrane. The decomposition of interaction energy from MD simulations analysis also confirmed the selectivity of phytochemicals from selected medicinal plants including Tylophorine, Vinblastine and Vincristine, and its anti-malarial potential was elucidated based on the conformation and dynamic differences observed between the residues in the PfMDR1 active site.
Figure 2: Structural superimposition of PfMDR1 complexes with Phytochemicals before and after MD (5 ns)
Figure 3. In vitro plasmodial activity of 3D7 strain (Schizont maturation assay)
This computational hypothesis was validated by different ligand-based approaches which correlated with the in vitro inhibitory activity of phytochemicals (Schizont maturation assay for drug sensitivity test) tested in our laboratory. Our in vitro results revealed significant morphological and biochemical alterations associated with the progressive inhibitory changes in the Plasmodium culture after the phytochemicals dosing. Thus, the present work emphasizes the need for selecting new targets and modules and screen natural compounds to combat the most rigorous modifications in Malaria research and aid in the treatment of the disease.
This work is supported by Gujarat State Biotechnology Mission (GSBTM), Department of Science and technology, Govt. of Gujarat, India.
H. H. G. van Es, S. Karcz, F. Chu, A.F. Cowman, S. Vidal, P Gros & E. Schurr (1994). Expression of the plasmodial pfmdr1 gene in mammalian cells is associated with increased susceptibility to chloroquine. Molecular and Cellular Biology 14, 2419-2428.
S.K. Patel, L.B.George, S. Kumar, H. N. Highland, Y.T. Jasrai, H.A. Pandya & K.R. Desai (2013). A computational approach towards the understanding of Plasmodium falciparum multidrug resistance protein 1. ISRN Bioinformatics, 1-15, doi:10.1155/2013/437168.
Saumya K. Patel 1, 2*
1Department of Bioinformatics