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Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) function is effectively inhibited by antifolates. The binding affinity of antifolates to PfDHFR-TS is reduced due to mutations in its active site. In the present study, 33 analogues of Methotrexate (MTX), Trimetrexate (TMX), Raltitrexed (RTX) and Pemetrexed (PTX) were designed and evaluated for interaction with PfDHFR-TS by in silico methods. Analyses of drug candidates were performed by generating their docking complexes with quadruple mutant crystal structure of PfDHFR-TS using Molecular Operating Environment (MOE). Initially eight top scoring complexes and then finally two (MTX04 and PTX03) were found suitable for further optimization based on interaction pattern with active site amino acids. Analyses of structural characteristics, binding energy calculations and interaction patterns of MTX04 and PTX03 with DHFR and TS domains respectively as best drug candidates. The comparative docking studies of these two compounds with human proteins provided a strong evidence of selectivity for MTX04 as effective antimalarial drug candidate. It is considered that the drug will inhibit the activity of folate pathway and it will be effective source to control malaria.
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