Feb. 27, 2020

Zoom meeting recording: https://ucl.zoom.us/rec/share/2cFcfpLNzU9IfZ2d6B7lBPUMRtrkT6a80CBL-aAJyU0h-J0zDY3aoMQWQh34aoM-

Relevant GH Issue: #18

Attendees

Tobias K., Lizbe K., Frank v. D. (Diamond)

Chris S. (Cambridge MedChem Consulting)

Chris D. (Univ. of Warwick)

Joe E. (Northeastern)

Dana K., Fahima I., Mat T. (UCL)

1. Chemistry summary (Dana/Fahima)

• Many compounds synthesized are closely related to hits with binding interactions preserved
• ACTION ITEM: DANA/FAHIMA send original hit compounds to TOBIAS/LIZBE for re-screening and validation

2. Original MurE screen (Tobias/Lizbe)

• All fragment analogues could be seen on electron density maps (Resolution ~ 2Å).
• Screening conditions:

Concentration ~50 mM

pH ~5.5

Crystal form Apo

Additives PEG, iPrOH

3. Modeling (Joe/Chris S.)

• Not useful for ranking or scoring but can be useful for looking at ligand geometry or target hotspots
• Potentially useful to look at ligand conformations and overlay
• Think about ring electronics and pKa of basic Ns in compound design. Potential loss in activity even with subtle changes.

4. New MurE pocket (Tobias/Lizbe/Frank)

• Screened approx 100 compounds
• Three compounds bind, causing a conformational shift in an α-helix, potentially disrupting substrate binding site and creating a new pocket
• Is this pocket conserved across Mur ligases/across species? Is this a potential strategy for Mur inhibition?
• ACTION ITEM: TOBIAS post results and pose this question for contributions on GitHub

5. MurD screening (Chris D.)

• Becca (Ph.D. student) working on replicating screening conditions
• Warwick lab can evaluate enzyme inhibition eventually but need the assay to be higher-throughput and able to detect weaker binding
• ACTION ITEM: DANA/FAHIMA send elaborated fragments and original hit compounds to CHRIS/BECCA for MurD screening

6. Closing

• ACTION ITEM: Further discussion of long-term budget and project management with MAT/CHRIS/FRANK/ETC.