Submission Details

Design Rationale:

Protein model x967: Sidechains of M49 and M165 have rotated to create more open pocket. Sidechain of N142 also flipped providing different H-bond opportunities. Fragment expansion: Ligands based on extension of pyridyl fragment of x107 into pocket between M49 and M165 using position of benzyl group of x72 as an initial guide. Fragments found by searching REAL database, various sets aligned in Pharmit using x967 receptor model and x107 and x72 ligands to define pharmacophore features. Top set screened through SeeSAR and N-[4-(hydroxymethyl)pyridin-3-yl] linked to cyclohexane identified as good central scaffold with many analogues already listed in REAL database. Further trial mods tested within SeeSAR identified 5 similar analogues also available from Chemspace REAL database. I then played with the best molecule in SeeSAR trialling various alternative elaborations instead of the hydroxymethyl substituent on the pyridine ring.

Other Notes:

First 5 of submitted set are all listed in Chemspace REAL database. This set all span from nM to low uM in SeeSAR affinity estimate. Chemspace IDs: CSCR00015600274 / Enamine Z1551628986 CSCR01640577599 / Enamine Z3542454033 CSCR00029367120 / Enamine Z1784165492 CSCR00045253863 / Enamine Z2635303491 CSCR00253153649 / Enamine Z2480367211 Cpd6 is not listed in the REAL database, but switching hydroxymethyl substituent for hydroxy-ethyl methyl-urea looks particularly good with the -OH sitting nicely between the mainchain oxygen of L167 and sidechain oxygen of E166. SeeSAR predicted affinity low-mid nM. Cpd6 SeeSAR model uploaded.

Inspired By:

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