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. 1. Introduction 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 including India. WHO reported an estimation of 216 million malaria cases worldwide in 2010 and around 1.5 million confirmed cases annually with 50% accounting for P. falciparum resistance according to the National Vector Borne Disease Control Programme (NVBDCP), India, 2011 [1, 2]. Recent studies have showed a strong association between chloroquine-resistant strains and the molecular changes in P. falciparum multidrug resistance protein 1 (PfMDR1) [3, 4]. PfMDR1 is a member of the ATP-binding cassette (ABC) superfamily and a transporter protein involved in small molecule trafficking. The functional polymorphisms encoded by pfmdr1 gene mutations lead to the development of resistance against leading antimalarial agents including chloroquine [5]. PfMDR1, a transmembrane glycoprotein and a homologue of P-glycoprotein 1 (P-gp1), is classified under the protein superfamily, ABC transporters, which act as efflux pumps that help in substrate translocation including the
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