If you\u2019d like to collaborate with me, send me an email.<\/p>\n\n\n\n\n \n
In terms of drug design, there\u2019s 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\u2019s life cycle. In particular, disabling methionine prevents the initiation of protein synthesis making it even more attractive.<\/p>\n\n\n\n
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<\/em> 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\u2019ll be publishing some of the promising structures in a future post. The authors of the X-ray co-crystal structure of the Leishmania <\/em>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 <\/em>but not Trypanosoma <\/em>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.<\/p>\n\n\n\n If you\u2019d like to collaborate with me, send me an email.<\/p>\n\n\n\n\n \n
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