Liver-stage Quantum Components.

<p>Quantum similarity of <b>A.</b> GNF-Pf-1498 and the quinoline-macrolide hybrid <b>B.</b> cethromycin that is related to CHEMBL440116 as well as chemical structures of <b>C.</b> GNF-Pf-1498 and <b>D.</b> cethromycin.</p

<i>in vivo</i> inhibition.

<p>10,000 sporozoites were inoculated by tailvein injection and mice were sacrificed 40 hours later, livers were harvested, placed in RNAzol and parasite levels determined by realtime PCR from cDNA from reverse transcription. Relative fluorescent units were compared to control to determine percent inhibition. Cethromycin CET was administered only once while the other drugs were given twice 24 hours apart from each dose. Two drugs related to CET, quinolone (QN) and erythromycin (ERY), had only marginal effect on parasite growth. CET’s effectiveness increased with dosage, reaching 60% reduction at 50 mg/kg. CET was also able to eliminate parasite infection when combined with low dose of PQ. All three novel compounds (T0507-9950, T5531873, T0510-7064) demonstrated significant inhibitory effect on parasite proliferation. Error is standard error of mean of three mice with real time PCR performed in duplicate for transcript levels in each mouse. B. Actual log values of relative fluorescent units from controls, cethromycin 12 mg/kg, primaquine 15 mg/kg and in combination are depicted. The combination has a 4 fold drop in relative fluorescent units compared to primaquine.</p

Summary of quantum scores with molecule identifications and reference molecules for scoring.

<p>Summary of quantum scores with molecule identifications and reference molecules for scoring.</p

Matching quantum scores of input and output molecules from cyclosporine.

<p>Matching quantum scores of input and output molecules from cyclosporine.</p

Matching quantum scores of input and output molecules from monesin and telithromycin.

<p>Matching quantum scores of input and output molecules from monesin and telithromycin.</p

Compound Structures from Quantum modeling.

<p>Chemical structures of CHEMBL440116 and four other identified molecules which were acquired and tested.</p

Malaria-Infected Mice Are Completely Cured by One 6 mg/kg Oral Dose of a New Monomeric Trioxane Sulfide Combined with Mefloquine

Sixteen new anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in <i>Plasmodium berghei</i> infected mice. Of these 16 new anilides administered orally as one 6 mg/kg dose combined with 18 mg/kg mefloquine hydrochloride, only sulfide 3-arteSanilide <b>12d</b> was completely curative: on day 30 after infection, all mice in this group had no detectable parasitemia, gained as much weight as the uninfected control mice, and behaved normally

Complementarity Between a Docking and a High-Throughput Screen in Discovering New Cruzain Inhibitors

Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99% of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1% of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone

Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A

Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, (<i>R</i>)- and (<i>S</i>)-2-((2-chlorophenyl)­(2-(piperidin-1-yl)­ethoxy)­methyl)-1<i>H</i>-pyrrolo­[3,2-<i>b</i>]­pyridine-7-carboxylic acid (compounds <b>N51</b> and <b>N52</b>) and (<i>R</i>)<i>-</i> and (<i>S</i>)<i>-N</i>-(1-(3-isopropyl-1<i>H</i>-pyrazole-5-carbonyl)­pyrrolidin-3-yl)­cyclopropane­carboxamide (compounds <b>N54</b> and <b>N55</b>). In vitro, the <i>S</i> enantiomer of the <b>N51</b>/<b>N52</b> pair (<b>N52</b>) and the <i>R</i> enantiomer of the <b>N54</b>/<b>N55</b> pair (<b>N54</b>) exhibited about 4- to 5-fold greater binding affinity. The more potent enzyme inhibition of KDM5A by the <i>R</i>-isoform for the cell-permeable <b>N54</b>/<b>N55</b> pair translated to differences in growth inhibitory activity. We determined structures of the KDM5A catalytic domain in complex with all 12 inhibitors, which revealed the interactions (or lack thereof) responsible for the differences in binding affinity. These results provide insights to guide improvements in binding potency and avenues for development of cell permeable inhibitors of the KDM5 family

Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A

Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, (<i>R</i>)- and (<i>S</i>)-2-((2-chlorophenyl)­(2-(piperidin-1-yl)­ethoxy)­methyl)-1<i>H</i>-pyrrolo­[3,2-<i>b</i>]­pyridine-7-carboxylic acid (compounds <b>N51</b> and <b>N52</b>) and (<i>R</i>)<i>-</i> and (<i>S</i>)<i>-N</i>-(1-(3-isopropyl-1<i>H</i>-pyrazole-5-carbonyl)­pyrrolidin-3-yl)­cyclopropane­carboxamide (compounds <b>N54</b> and <b>N55</b>). In vitro, the <i>S</i> enantiomer of the <b>N51</b>/<b>N52</b> pair (<b>N52</b>) and the <i>R</i> enantiomer of the <b>N54</b>/<b>N55</b> pair (<b>N54</b>) exhibited about 4- to 5-fold greater binding affinity. The more potent enzyme inhibition of KDM5A by the <i>R</i>-isoform for the cell-permeable <b>N54</b>/<b>N55</b> pair translated to differences in growth inhibitory activity. We determined structures of the KDM5A catalytic domain in complex with all 12 inhibitors, which revealed the interactions (or lack thereof) responsible for the differences in binding affinity. These results provide insights to guide improvements in binding potency and avenues for development of cell permeable inhibitors of the KDM5 family