Thousands of chemical starting points for antimalarial lead identification

Abstract

Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.

Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses

“…Therefore, several subtle yet crucial differences between host and pathogen tyrosyl-tRNA synthetase active sites (Fig. 2b-d) present a window for exploiting the malaria parasite enzyme for structurebased inhibitor discovery-consistent with recent high-throughput chemical library screening data 31 .…”

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

“…5 Recently, researchers at GlaxoSmithKline (GSK) published the structures of 13 533 hits from the screening of nearly 2 million compounds that inhibited malaria parasite growth by at least 80% at 2 μM concentration. 6 These hits were further analyzed using cheminformatics to identify 47 series of high-quality starting points for lead optimization. 7 The series 3 included 74 compounds based on a hydroxyethylamine scaffold that is characteristic for plasmepsin inhibitors.…”

“…The interactions in the S1−S4 and S1′ pockets are predominantly hydrophobic, while a few H-bond interactions are formed with the more central groups of the inhibitor, i.e., between the benzamide and Gly216 and the N,Ndipropylamide and Ser218 (Chart 2c). Additionally, the secondary amino group seems to interact simultaneously with 6 within the Active Site of Plm II a a (a) X-ray crystal structure showing the ligand and residues located within 4 Å from it as stick models (colored in yellow and cyan, respectively). (b) 2F o − F c electron density of the bound ligand contoured at 1σ.…”

“…Compound 1SR showed somewhat higher activity to inhibit the growth 3D7 parasite strain in erythrocytes compared to GSK LDH assay. 6 This deviation can be due to the different assays used to monitor parasite growth. The results of parasite growth inhibition of compounds 1SS, 1SS, 3, and 16−18 again showed a clear correlation between parasite growth suppression and Plm IV inhibition, and not with Plm I or Plm II inhibition.…”

Discovering New Transmission-Blocking Antimalarial Compounds: Challenges and Opportunities

“…Phenotypic screening of more than seven million compounds for activity against the asexual blood stage pathogen has resulted in new chemical entities entering clinical development to ensure continued population of the drug development pipeline (www.mmv.org) [5,18]. Similar approaches have been proposed to discover transmission-blocking compounds by screening against primarily mature gametocytes but this has been very difficult compared to screening asexual blood stages, particularly because the apparent quiescence of mature gametocytes has hampered the development of cell-based screening assays specific to stage V gametocytes [19].…”