In terms of drug design, there’s the important question of what biologically relevant molecule to target for therapeutic effects. In terms of leishmanial drug discovery, a very interesting new co-crystal structure was deposited in the protein data bank. The structure an allosteric inhibitor of Leishmania major co-crystallized with methionyl-tRNA synthetase. This interesting X-ray structure represents a new opportunity to apply virtual screening for discovery of new allosteric inhibitors of Leishmanial tRNA synthetase. In terms of mechanisms of action for anti-parasitic drugs, I particularly like inhibitors of RNA translation to protein. These types of molecules, such as the ligands of methionyl-tRNA synthetase recently co-crystallized, strike at the heart of a pathogen’s life cycle. In particular, disabling methionine prevents the initiation of protein synthesis making it even more attractive.
My preliminary work shows that several molecules score similarly or better to the co-crystal ligand after virtual screening of several hundred thousand small molecules with molecular weights between 325 and 400. Choosing molecules for in vitro assay among the top scoring compounds is a bit more complicated than prioritizing the top scoring compounds. A new allosteric inhibitor has to make very similar contacts for proper allosteric modulation of the tRNA synthetase. I’ll be publishing some of the promising structures in a future post. The authors of the X-ray co-crystal structure of the Leishmania methionyl tRNA synthetase with the allosteric inhibitor (PDB ID 6SWX) originally identified the hit compound through a High Throughput Screen (HTS) of adenosine analogs. This strategy successfully found a useful allosteric inhibitor for Leishmania but not Trypanosoma methionyl tRNA. Perhaps the virtual screen can diversify scaffolds which can bind to this protein, as well as identify a scaffold which can bind to multiple parasitic tRNA synthetases.
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Short movies of the binding mode of the co-crystal ligand of 6SWX and the redocked ligand (blue)
