Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/ALP-POS-c0ee8219
I’ve modelled the pharmacophores in the 4MDS and other templates for docking and suggested a combination of the acids and amines below to make simple amides. The charge density on the 5-membered aromatic ring is optimised using QM to increase hydrogen bond strength with HIS163 and the adjacent amide picks up the rest of that local pharmacophore at the GLU166 backbone NH. Adjacent to this is a nice electronegative diad and GLU166 backbone amine may H-bond to the protonated amine (in one structure for example). There is a chiral centre and one enantiomer is better than the other, but both enantiomerrs dock reasonably well. Unfortunately the amine in the bicyclo [3.6.0] system may compete with itself to form an amide, but it should be more sterically hindered and the lesser product. (note the extra bits are lone pairs). This will hopefully inform the more complex design we are working on with Richard and Holly on at Leeds.
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