The ChEMBL-og

Just a quick (but surprisingly wordy) follow up on the previous post on the drug profiling against malaria. Drug repurposing/reuse/rescue offers great potential for the enhancement of patient lives and also is a quick way of pushing new therapies through the clinic. It is often see as low cost and low risk, is highly translational in terms of the research, and there are some stunning success stories. It is therefore very sensible to screen known drugs in assays of interest, which is exactly what was done in the recent, excellent, Science paper. The compounds in Table 1 of the paper are reported at the highly active set (and these exclude already known established antimalarial drugs which all pass the selection criteria used for compounds in this table, this seems a pretty good and pragmatic place to set cutoffs). For use as an widely-used and developing world-applicable antimalarial (co)-therapy I would have imagined that ideally you would want established well tolerated daily dosi...

I came across this interesting paper from earlier this year - " HIV proteinase inhibitors target the Ddi1-like protein of Leishmania parasites ", published in FASEB J . HIV protease inhibitors were known to decrease levels of Leishmania in vivo , but the molecular target was not known. This paper shows that HIV-1 proteinase inhibitors are probably functional inhibitors of Ddi1 from Leishmania spp.  Nelfinavir (the structure above) is a 440 nM IC 50 inhibitor of L. major Ddi1 (and weaker against the human ortholog 3.3 uM). This is on the face of it, a lovely example of drug repositioning - the use of a drug for a new, and in this case, a non-obvious use. HIV-1 PR (UniProt: Q9YQ34 ) and Ddi1 (UniProt: A4H334 ) are both aspartyl proteinases (Pfam: CL0129 ), share a common mechanism, and overall architecture (although HIV-PR is a homodimer, and Ddi1 is a single chain containing two 'copies' of the HIV-PR sequence). There is a human Ddi1 ortholog as well (UniProt: Q8...