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Cambridge MedChem Consulting

The quality of the crystal structure is critical

Crystal structures are not perfect, and it is important to understand the limitations and not assume as Derek Lowe once put it, they are a "message from God". It might be worth reading the section on structure-based design.

With this in mind I thought I'd flag this message from Bobby Glen (Cambridge) here.

Hi, we’re still (Jason at CCDC) porting GOLD to our HPC system so we can basically parallel dock. We should be able to dock and score early next week I hope, There are a few issues we also are addressing wrt the crystal structures, Gerard Bricogne at Global Phasing is kindly re-refining the published structure from the ED, this hopefully will inform us of for making some changes to the orientation/pKa and tautomers of the histidines and some of the other AAs. It’s very difficult to ‘see’ hydrogen in x-ray and these are inferred from the structure. We need to be sure we have a decent model of this (at physiological pH) before doing all the calculations. An example is H163, which is in the binding site, and is critical to a few of the interactions seen in ligands for this class of proteases. Automated hydrogen addition can be problematic.