School Of Basic And Applied Sciences

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    Novel potent inhibitors of Plasmodium vivax dihydrofolate reductase: An in silico antimalarial drug discovery
    (Association of Pharmaceutical Teachers of India, 2018) Pushpendra, Singh; Kushwaha, Prem Prakash; Shashank, Kumar
    Objectives: In the present study, we targeted the dihydrofolate reductase enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate which is required for the purines and pyrimidine synthesis. Malaria is one of the severe diseases throughout the world caused by blood-borne parasite Plasmodium vivax. Materials and Methods: Eighty-five parthenin analogs were docked against P. vivax and Homo sapiens dihydrofolate reductase proteins (PDB 2BL9 and 1KMS respectively) by using Maestro 9.6 program to evaluate the binding affinities of ligands with the protein. Results and Discussion: Docking analysis revealed some best hit ligands against P. vivax such as CID3467446 and CID56671343 but not inhibited the mammalian dihydrofolate reductase. The Dock score of parthenin analogs ranged from -7.31 to -9.3 while for standard dihydrofolate reductase inhibitors it was -4.78 to -8.04. Structural analysis of docked complexes of selected parthenin like compounds with P. vivax and mammalian dihydrofolate reductase revealed the involvement of Arg 115, Leu 136, Lys 138, Gly 175, Ser 117, Gln 177 and Ile 7, Ala 9, Thr 56, Ile 60, Pro 61 amino acid residues respectively in strong interactions. Absorption, distribution, metabolism, and excretion properties of best-docked compounds were predicted using QikProp application of Maestro 9.6. The results indicated that all the best-docked lead compounds followed Lipinski?s rule of five. Conclusion: Based on the results of the present study it has been concluded that parthenin like compounds may serve as potent dihydrofolate reductase inhibition based anti-malarial drug lead. ? 2018, Association of Pharmaceutical Teachers of India. All rights reserved.
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    Conserved structural chemistry for incision activity in structurally non-homologous apurinic/apyrimidinic endonuclease APE1 and endonuclease IV DNA repair enzymes
    (2013) Tsutakawa, Susan E.; Shin, David S.; Mol, Clifford D.; Lzumi, Tadahide; Arwai, Andrew S.; Mantha, Anil K.; Szczesny, Bartosz; Ivanov, Ivaylo N.; Hosfield, David J.; Maiti, Buddhadev; Pique, Mike E.; Frankel, Kenneth A.; Hitomi. Kenichi; Cunnigham, Richard, P.; Mitra, Sankar; Tainer, John A.
    Non-coding apurinic/apyrimidinic (AP) sites in DNA form spontaneously and as DNA base excision repair intermediates are the most common toxic and mutagenic in vivo DNA lesion. For repair,APsites must be processed by 5' AP endonucleases in initial stages of base repair. Human APE1 and bacterial Nfo represent the two conserved 5' AP endonuclease families in the biosphere; they both recognize AP sites and incise the phosphodiester backbone 5' to the lesion, yet they lack similar structures and metal ion requirements. Here, we determined and analyzed crystal structures of a 2.4 ? resolution APE1-DNA product complex with Mg2+ and a 0.92 ? Nfo with three metal ions. Structural and biochemical comparisons of these two evolutionarily distinct enzymes characterize keyAPE1catalytic residues that are potentially functionally similar to Nfo active site components, as further tested and supported by computational analyses. We observe a magnesium-water cluster in the APE1 active site, with only Glu-96 forming the direct protein coordination to the Mg2+. Despite differences in structure and metal requirements of APE1 and Nfo, comparison of their active site structures surprisingly reveals strong geometric conservation of the catalytic reaction, with APE1 catalytic side chains positioned analogously to Nfo metal positions, suggesting surprising functional equivalence between Nfo metal ions and APE1 residues. The finding that APE1 residues are positioned to substitute for Nfo metal ions is supported by the impact of mutations on activity. Collectively, the results illuminate the activities of residues, metal ions, and active site features for abasic site endonucleases.