Study of a Novel Pattern of MDR1 protein and its Significance as Drug target against Malaria

Author Name: *Susanta Kumar Panda,Amit Kumar
Author Email: susantapanda.pkd@gmail.com

Abstract

The increased incident and rapid spread of drug resistance in Plasmodium falciparum has become a major public health obstacle in India. Multi-Drug Resistance1 (MDR1) Protein has been one of the major protein to resist various types of antimalarial drugs. There is a need to develop new drugs against malaria combating the drug resistance ability of the plasmodium. The current research is based on the Comparative study of MDR1 protein in different Model organisms using Insilco approach to determine the potential drug target for malaria treatment. MDR1 protein from different plasmodium species and few higher vertebrates were taken for comparative study. Multiple sequence alignment (MSA), domain and disorder prediction were performed to study the patterns which are biologically significant and conserved in the protein. Through our analysis we found a specific pattern which is repeated twice in MDR1 protein of plasmodium species and the same pattern was even found in higher vertebrates. The study of this pattern signifies a specific variation in the plasmodium species that infects rodents which may illustrates uniqueness of this plasmodium species exhibiting different pathogenicity style. The conservation among the plasmodium species and higher vertebrates were studied. The mutation probability at this region might be the possible reason for drug resistance. Any mutation at this conserved region can be a potent target site. This knowledge therefore, will facilitate the rationale to design a new effective drug as well as check the emergence of multi-drug resistance.

Introduction

Malaria caused due to Plasmodium Falciparum is dangerous malignant malaria that takes millions of lives every year on a world wide scale. This Parasite has managed to develop resistance to many antimalarial drugs. The search for the molecular basis of drug resistance in the parasite has lead to the identification of the PFMDR1 and PFCRT genes, which have been associated with resistance to the Chloroquin and other antimalarial Drugs in plasmodium falciparum malaria[1-2]. Resistance to
anti-malarial drugs is one of the major obstacles to effective malaria treatment and control. For the better understanding of the mechanism by which the plasmodium operate and develop resistance are necessary to implement new strategies to defeat this deadly disease. Although multilateral malaria research programmes are currently in progress to study the molecular biology of the parasites, a definitive explanation for the drug resistance remains elusive. New approaches like the use of rodent plasmodia represent interesting in vivo models that could help to understand better the molecular aspect of drug resistance in the plasmodia. All over world particularly in endemic areas plasmodium falciparum resistant to chloroquin and sulphadoxine-pyrimethamine is common. In India as per the World Health Organisation (WHO) guideline National Vector Disease Control programme has undertaken [3]. At present ACT (AS+SP) combination Drug Therapy is being implemented in 117 districts of high endemic districts of States [4-5]. Protein interactions and specific Amino Acid position changes and Domain analysis of Membrane transporters, such as the Plasmodium falciparum multi drug resistance 1(pfmdr1) and the Plasmodium chloroquine resistant transporter (pfcrt), which is a member of the ABC superfamily, have been identified as key contributors in decreasing susceptibility to several anti-malarial drugs[6]. Research to identify additional potential contributors to Plasmodium drug resistance has lead to the identification of new candidate transporter Proteins, some of which belong to the ABC transporter super family. Alteration in the parasitic membrane protein PFMSP, PFCRT and PFMDR1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation. The PFMDR1 Protein was classified under the ABC transporter super family based on the sequence and organization of their conserved Amino Acid binding domains [7]. Characteristic motifs within these Amino Acid binding sites are found in the majority of AAA Domains. This review highlights the patterns of MDR1 protein.

Conclusion

Drug resistance is an important problem in Falciparum Malarial diseases, which is very difficult to tackle by the limited number of drugs available. A good knowledge on drug resistance can help the researcher to find strategies to increase the efficacy. From the overall analysis we traced a novel pattern that was conserved among the species and was in two repeats in a single protein sequence. The pattern gave significant information about the uniqueness of Rodent infected plasmodium falciparum and predicting the possible potent drug target for malarial treatment.

 

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