Paper Title :Computational Study of Plasmodium Falciparum Dihydrofolatereductase-Thymidylate Synthase (PfDHFR-TS) Enzyme as Antimalarial Drug Resistance Mutation

Author :Alaa Mohammed Khalaf, Hani Mohammed Ali, Yasir Anwar, Thana Khalid Mohammed Khan, Ahmad Firoz

Article Citation :Alaa Mohammed Khalaf ,Hani Mohammed Ali ,Yasir Anwar ,Thana Khalid Mohammed Khan ,Ahmad Firoz , (2019 ) " Computational Study of Plasmodium Falciparum Dihydrofolatereductase-Thymidylate Synthase (PfDHFR-TS) Enzyme as Antimalarial Drug Resistance Mutation " , International Journal of Advances in Science, Engineering and Technology(IJASEAT) , pp. 12-16, Volume-7,Issue-1

Abstract : Malaria is a significant infectious disease caused by Plasmodium parasites infection. The global estimation in 2015predicted that malaria infected 200 million and killed 438,000 people. Some of the anti-malarial drugs act by targeting Plasmodium falciparum dihydrofolate reduct ase-thymidylate synthase (PfDHFR-TS) enzyme. However, mutations caused by P. falciparum resistance disrupt the efficacy of inhibitory drugs that target PfDHFR-TS, resulting in reducing the effectiveness of the treatment, and thus sustaining the pathogenic activity. Therefore, this study was carried out to firstly, build a mutant model of the target enzyme and compare it with the wild-type structure. Secondly, determine the protein core within the primary protein structure of the wild-type PfDHFR-TS in order to look for any properties that may indicate drug gable sites within this target; and finally investigate the position of the antimalarial drug resistant mutations relative to the protein core. The protein core is defined as the loop ends (locks), in accordance to the Berezovsky closed loop hypothesis of protein folding, plus contact sets. Different powerful computational tools were used including modeller program to build a 3D mutant model, as well as a specialized server and Per1 script available at Cont Pro to identify the locks and residues contact sets. A 3D mutant model of PfDHFR-TS was successfully built showing four mutations. The comparison between the structures of mutant and wild-type showed no significant changes. Within the pfDHFR-TS wild-type structure, the core was determined from the lock residues 18, 39 connected with 50 residues within 6 Angstrom atomic contact. Significantly, the mutations were located far away from the core. Taken together, the present study provides an important opportunity to improve our understanding of PfDHFR-TS antifolate target and therefore the potential development of new effective drugs against malaria. Index Terms- PFDHFR; Antimalarial Drug Target; Drug Resistance; Mutation; Closed Loop Hypothesis

Type : Research paper

Published : Volume-7,Issue-1

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