Computational protocol: Structure-Based Design of Pteridine Reductase Inhibitors Targeting African Sleeping Sickness and the Leishmaniases†

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Protocol publication

[…] Compounds were dissolved at 100 mM in DMSO and screened against LmPTR1 and TbPTR1 with H2B (10 mM in 0.1 M NaOH) as the substrate. The IC50 values were determined from dose−response plots using SigmaPlot() adjusted with Morrison’s equation for tight-binding inhibition.()Ki values were derived from the IC50 values using the equation for competitive inhibition as published.() [...] X-ray data were collected in-house using a Rigaku Micromax 007 X-ray generator equipped with an Raxis IV++ detector, at station 14.1 of the Synchrotron Radiation Source (SRS), Daresbury, U.K., and beamlines BM14, ID23-1, ID23-2, and ID29 of the European Synchrotron Radiation Facility (ESRF), Grenoble, France ( Tables S1−S3). Data were processed with the CCP4 software suite.() X-ray images were integrated and scaled with MOSFLM() and SCALA() or XDS and XSCALE.() Structures were solved by molecular replacement() using TbPTR1 as the starting model.() Several rounds of restrained refined were carried out using REFMAC5() together with inspection of electron and difference density Fourier maps, model manipulation, and identification of solvent ions and ligands with COOT.() Figures were generated with PyMol.() […]

Pipeline specifications

Software tools SigmaPlot, CCP4, iMosflm, XDS, REFMAC5, Coot, PyMOL
Applications Miscellaneous, Small-angle scattering, Protein structure analysis
Organisms Trypanosoma brucei, Cyclophiops major
Diseases Leishmaniasis, Trypanosomiasis, African
Chemicals Pteridines