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Drug Discovery


Figure 4


3D structure of ACL tetramer at 3.7A using cryo-EM. ADP in yellow, inhibitor in Tyrian purple. Image based on PDB-


entry 6o0h created with Pymol by Hans Raaijmakers


Enzymes Cryo-EM structures reveal new, potent, selective inhibitor of parasite enzyme Visceral Leishmaniasis (VL) or Black Fever is one of the most severe tropical diseases with up to 40,000 deaths annually. Present treatments have serious drawbacks of prolonged treatment dura- tion and low tolerability, with sometimes high ter- atogenic effects. Also, the significant geographical variations in effectiveness have been noticed. The additional serious drawbacks are high costs of treatment and strict conditions for cold storage. A new GSK preclinical candidate inhibits chy-


motrypsin-like activity over the human enzyme and selectively inhibits the parasite enzyme. The objective of this research was to identify a


low-cost, safe, effective, oral, short-course drug for VL based on inhibition of parasite enzyme. High-resolution cryo-EM structures revealed


site. While the crystallographic structure took many years to solve and soaking in compounds was not successful, the cryo-EM was the ultimate method of choice. In addition, cryo-EM structure supported mechanistic interpretation of ProTx2 complex shifting the activation of Nav and phar- macologically stabilising the closed-channel state (Figure 2).


Figure 5 Electron density map obtained


from cryo-EM (wireframe). The corresponding receptor-insulin complex structure is overlaiD.


Image based on PDB-entry 6ce9 created with Pymol by Hans Raaijmakers


previously undiscovered binding site for inhibitors of chymotrypsin-like activity. (Figure 3)4.


Cryo-EM reveals allosteric site for enhanced ‘druggability’ of ATP-citrate Lyase ATP citrate lyase (ACLY) is a cytosolic enzyme that catalyses conversion of mitochondrially-derived citrate into acetyl-CoA and oxaloacetate, thereby defining the first step in the cellular fatty acid syn-


12


Drug Discovery World Winter 2019/20


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