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Advancement in computational biology leads to improve the efficacy for new compounds to cure the diseases. Malaria is the most virulent diseases and causing millions of deaths annually, especially in developing and under-developed countries. Plasmodium falciparum dihydrofolate reductase (.P/DHFR) is one of the most important drug target for different antifolates. Pyrimethamine with sulphadoxine complex is the most recommended and efficient antifolate prescribed against R/DHFR. But malarial parasites have developed resistance against this drug due to the point mutations in P/DHFR. This study focus to design a novel antimalarial drug (analog) against mutated P/DHFR by considering the 'in silico approaches. The new antimalariai. drugs were designed by the addition/substitution of different functional groups and molecules in parent compound of pyrimethamine. The docking studies of newly designed compound and pyrimethamine with mutated receptor protein of P/DHFR were performed by using different docking servers. Various in silico therapeutic calculations for novel antimalarial compound and pyrimethamine were executed using computational approaches. The basic of ligand properties, docking results, energy calculations and drug score favor indicated that the new antimalarial drug compound have potential to show better efficacy than pyrimethamine. This designed analog could be used for preclinical test and have the potential to eradicate P. falciparum. [ABSTRACT FROM AUTHOR]

Multi-drug resistant malaria parasite promotes the search of new analogues against mutated drug targets. Plasmodium falciparum cytochrome b (PfCytochrome b) was a promising drug target but resistance linked to the mutation has been reported. Different combinations of point mutations have been observed in atovaquone-resistant strains of Plasmodium falciparum (P. falciparum). The crystal structure of wild type and mutant PfCytochrome b has not been reported till present. In current study, the analyses and characterization of mutated primary sequences and generation of 3D structure for wild type and mutated PfCytochrome b taken into account. The spotlight of this study is to generate 3D structural model of the PfCytochrome b by utilizing in silico methods. The template based protein modeling servers were considered for 3D structural modeling and finally selected structures were validated by utilizing computational tools. Docking studies revealed that conformational changes in active site are potentially associated with resistance development due to point mutations. These findings are useful for further structure based investigations to design new drugs against mutated protein. [ABSTRACT FROM AUTHOR]