The number of compounds found to demonstrate inhibition at 10μM overall and with respect to the two different methods of ranking compounds.

<p>The number of compounds found to demonstrate inhibition at 10μM overall and with respect to the two different methods of ranking compounds.</p

The distribution of tested and active compounds within the submitted (a) Vina ranked and (b) custom ranked compounds.

<p>For each ranking 1000 compounds were submitted from which the TDT organizers sampled a total of 167 compounds for testing. Within the Vina ranking, better scoring compounds are more likely to be active. No such enrichment is observed for the custom ranking.</p

A pharmacophore derived by a student from a structure of DHODH bound to an inhibitor (PDB 3I65).

<p>The pharmacophore consists of hydrophobic features (green spheres) and a hydrogen donor feature (white sphere). This pharmacophore was used as part of a virtual screen for novel inhibitors.</p

Pose prediction results.

<p>The crystal structure of compound 6 (pink sticks) bound to its receptor (silver) is compared to the predicted poses. Pose alignments were obtained by aligning the crystal receptor with 3I65 using PyMOL [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134697#pone.0134697.ref022" target="_blank">22</a>]. (a) The pharmacophore-aligned pose has a heavy-atom RMSD to the crystal pose of 1.77Å while (b) the pose minimized with a flexible ARG-265 has an RMSD of 1.18Å.</p

Chemical structure of DHODH inhibitor 5-methyl-7-(naphthalene-2-yl-amino)-1H-[1,2,4]triazolo[1,5-a]pyrimidine-3,8-diium.

<p>The six pharmacophore features used to define the sparse model search space are labeled. Green labels refer to hydrophobic groups, blue labels refer to hydrogen bond features.</p

Query results for top four- and five-feature pharmacophore models.

<p>Query results for top four- and five-feature pharmacophore models.</p

The ZINCPharmer based interactive pharmacophore modelling interface used by the students to competitively develop an informative pharmacophore model.

<p>The ZINCPharmer based interactive pharmacophore modelling interface used by the students to competitively develop an informative pharmacophore model.</p

Pose prediction of compound 6.

<p>Receptor structure and binding site residues of 3I65 are shown in blue. Compound 6 is shown in magenta sticks. (a) Compound 6 aligned to the pharmacophore of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134697#pone.0134697.g001" target="_blank">Fig 1</a>. The compound makes a hydrogen bond with HIS-185. (b) After minimization, the pose has twisted so that the hydrogen bond to HIS-185 is broken. (c) When the pharmacophore aligned posed is minimized with a flexible ARG-265, which sterically clashes with the initial pose, a less dramatic movement is observed and the hydrogen bond to HIS-185 is maintained.</p

Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening

Plasmodium falciparum dihydroorotate dehydrogenase (<i>Pf</i>DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, which the Plasmodium falciparum relies on exclusively for survival, has emerged as a promising target for antimalarial drugs. In an effort to discover new and potent <i>Pf</i>DHODH inhibitors, 3D-QSAR pharmacophore models were developed based on the structures of known <i>Pf</i>DHODH inhibitors and the validated Hypo1 model was used as a 3D search query for virtual screening of the National Cancer Institute database. The virtual hit compounds were further filtered based on molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. The combination of the pharmacophore and structure-based virtual screening resulted in the identification of nine new compounds that showed >25% inhibition of <i>Pf</i>DHODH at a concentration of 10 μM, three of which exhibited IC₅₀ values in the range of 0.38–20 μM. The most active compound, NSC336047, displayed species-selectivity for <i>Pf</i>DHODH over human DHODH and inhibited parasite growth with an IC₅₀ of 26 μM. In addition to this, 13 compounds inhibited parasite growth with IC₅₀ values of ≤50 μM, 4 of which showed IC₅₀ values in the range of 5–12 μM. These compounds could be further explored in the identification and development of more potent <i>Pf</i>DHODH and parasite growth inhibitors

Species-Selective Pyrimidineamine Inhibitors of <i>Trypanosoma brucei S</i>-Adenosylmethionine Decarboxylase

New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite <i>Trypanosoma brucei</i>. <i>S</i>-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of <i>T. brucei</i>. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a <i>T. brucei</i> AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for <i>T. brucei</i> AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood–brain barrier penetration. The medicinal chemistry program elucidated structure–activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of <i>Tb</i>AdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization