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Plasmodium Falciparum Malaria (PFM) infection is a leading source of life killing diseases such as Cerebral Malaria, Nephritis, Hepatic disorder and Severe Anaemia. In the current study, we use computational methods in order to improve our understanding of the complex disease interactions of Plasmodium Falciparum Malaria. Through our work we tried to emphasize the complexity of the disease and the key molecular players involved in its pathogenicity. We found one of the crucial genes named PFMDR1 in this study that proves to play an important role in the diagnosis and treatment of the disease. The protein encoded by this gene has been popularly reported for its drug resistance ability. Therefore, PFMDR1 protein is the preferential choice for inhibition to stop the drug resistance processing. PFMDR1 Gene characterization studies were performed. SNPs responsible for drug resistance and its corresponding Amino Acid change were studied. Mutational analysis and Biological significance of the mutations were analyzed. From the overall study, we found mutation N1042D plays prominent role in drug resistance. Hence, the 3D structure of mutated PFMDR1 protein was modelled. For inhibiting the action caused by the mutation, 120 Natural Chemical compounds which have the anti malarial property were selected. The compounds were screened for Druglikliness and Toxicity. 60 chemical compounds were finally screened. The chemical structures were further subjected to Geometry optimization and Energy minimization for standard confirmation of the chemical structures. MDR1 protein’s mutational site was explored to find out the critical interactions for inhibitor binding using molecular docking methodology. After several docking steps, Finally LAPACHOL compound with the binding energy -11.09444Kcal/mol was found to be the potent drug candidate which can efficiently interact with the mutational site thereby inhibiting the phenomenon of drug resistance in Plasmodium Falciparum. It should be noted that these predicted data should be validated using suitable assays for further consideration.
Infection by the malarial disease is curable and can be preventable but it is still the most important life threatening disease in the world wide. The current Consensus report that there are annually about 500 million clinical cases of malaria, 2-3 million severe attack and 1 million deaths, which is approximately equal 3000 death per day, estimated by the report in African country it takes every 30 second a life. Malaria remains uncontrolled not only in the developed countries but also in developing countries. Few important reasons can be emergence of the drug resistant parasite, widespread use of dichlorodiphenyltrichloroethane (DDT) insecticide resistant mosquito vector and non availability of suitable and effective malaria vaccine. The disease burden is increasing in almost all the tropical countries. Since malaria creates socio-economic problems and also causes large number of deaths, particularly among young children and pregnant women. The situation is becoming more difficult because the most widely used antimalarial drug chloroquine is losing its effectiveness. Plasmodium falciparum from Sub Saharan Africa started showing resistance to this drug in late 1950s which was followed in other parts of the World. In India, the chloroquine resistance was first reported from Assam in 1973 and had caused some epidemics since 7-8 years. Sulphadoxine-pyrimethamineis used as a second line of drug to treat uncomplicated chloroquine resistant falciparum malaria cases but recent past it is also noted that this drug is also showing its resistance all over India . Although various other antimalarial drugs are also being used but chloroquine and sulphadoxine – pyrimethamine remains the most widely used drugs. Molecular drug resistance profile of the parasite population consistent with a chloroquine and sulphadoxine-pyrimethamineis resistant phenotype strongly indicate that a police change to artemisinin based combination therapy (ACT) has to be considered in the near future. Standard treatment for malaria is combination therapy artimisinine and sulphadoxine or any other. Artemisinin combination therapy (ACT) and replaced former mono-therapy options in management of uncomplicated malaria as recommended by WHO . This review provides information on the molecular targets for these commonly used drugs, and also on mutations in these target genes which are associated with the development of drug resistance, Resistance against these drugs is being reported from all over the world wide,pfcrt, pf mdr-1[4,5,6,],(Chloroquine Resistence) dhps[7,8], dhfr(Sulfadoxine Pyremethemine) , PfATPase6 (artemisinin). High-level chloroquine resistance appears to require alterations in other genes such as P. falciparum multidrug resistance (pfmdr1) Polymorphisms K76T in pfcrt and N86Y, S1034C, N1042D, and D1246Y in pfmdr1 have been identified as being associated with chloroquine resistance, however the efficacy of this control strategy is hampered by the emergence and spread of drug resistant malaria which is the major challenge in the control of the disease at present. Therefore research efforts into the design and development of new antimalarial drugs, which are safe effective and affordable are of prime importance.
With the help of predicted models, the conformational changes due to mutations at the active site residues were determined. On the basis of docking score, it can be interpreted that the strict constraints resulting from such mutations could significantly alter the folding of the mutant protein and or the positioning of the Amino Acid residues. This may readily explain the loss of PFMDR1 activity thereby inhibiting the effect due to conversion of ASN to ASP. Also, how point mutations can dramatically alter the ability of drug binding which eventually may lead to differences among the mutants. Thus, we suggest that the mutant N1042D represented with high docking score may contribute to low-level drug resistance than other mutants. The findings suggest that redesign of the PFMDR1 Protein molecule to improve drug binding may be a viable approach to overcome resistance in especially for mutant with N1042D substitutions. Such studies will be helpful in better understanding about the mechanism of drug resistant. Detection of mutations at the active site of the target protein enables to gain novel insight into the drug-target interactions, leading to the rational design of more efficacious wonder drugs that not only shorten malarial therapy but also can prevent the emergence of drug resistance.
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