MurE Round 1
As discussed in Issue #16, no compounds sent as part of the follow-up on clusters 6 and 15 were shown to bind MurE.
The initial MurE fragment screen yielded OSA_000005 and OSA_000006 as fragment hits
Follow up fragments (47 compounds) were synthesised and sent to Diamond for evaluation in December 2019. Although these compounds share many structural similarities to the initial fragment hits, none were found to bind to MurE.
Rationale:
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The two fragments are synthetically simple hence we wanted to explore whether different aromatic tethers could be tolerated as fragments OSA_000005 and OSA_000006 both have the thiomorpholine 1,1-dioxide in common.
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Different amines moieties were also incorporated into the fragment analogues, some of which can form similar bonding interactions to thiomorpholine 1,1-dioxide.
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Different tethers were also investigated to try to maximise interactions to the target (amides, sulfonamides)
The initial MurE fragment screen yielded OSA_000007 and OSA_000008 as fragment hits
Follow up fragments (20 compounds ) were synthesised and sent to Diamond for evaluation in December 2019; the structures are shown below. Based on the binding pose of OSA_000007, two major points of modification were explored.
- A variety of analogs of the aminocyclobutanol moiety were made in hopes of finding a replacement that would be more synthetically tractable. Several of these compounds retained the H-bond donor distal to the pyrimidine core, which was shown to participate in binding to the target.
- Analysis of the binding pose of the pyrimidine portion of the molecule indicated that the 6-position methyl group was solvent-exposed, while the 2-position pointed into a pocket that could potentially be filled with larger substituents. To that end, a group of 2,4-disubstituted pyrimidines were synthesized.
However as with cluster 6, none were found to bind to MurE.
A few synthetic intermediates and isolated side products were also included in the shipment. It is less surprising that these compounds did not bind given that the structures are quite dissimilar to the original hit.
