Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/ALP-POS-8ed8d9ec
Alpha,
Would be worthwhile trying to avoid furans, thiophenes and pyrroles from a metabolism perspective. N-methylpyrazoles would be one possibility along with various phenyls, pyrazines and pyrimidines. Obviously depends on what is most synthetically tractable to test your hypothesis.
Joe
Hi @Joe
I would echo these concerns (especially with respect to pyrrole). The second of these two designs may be of interest (the first is a duplicate of a design from @alphalee and I kept the thiophene in order to allow comparison with the parent benzotriazole): PET-UNK-7374c256. The idea is to present an HB donor to E166 since similar interactions have been observed for other ligands, for example, AAR-POS-d2a4d1df-2.
@pwkenny @Joe I completely agree with your concerns, and sorry for the delay in replying!
This is the set that is actually being synthesized: https://postera.ai/covid/submissions/a3de0cb1-1500-4e90-9871-658309aa7086 @JohnChodera is also running FEP calculations on a larger library of benzotriazoles.
Hi @alphalee @mc-robinson @JohnChodera
I’ll make some comments on the compounds selected for synthesis in case this input is useful in interpreting subsequent assay results and I’ll also copy @Joe. As most of these are azoles, I’ll highlight the potential for CYP inhibition by azoles and it’d be a good idea to assess CYP inhibition early (i.e. before synthesizing large numbers of compounds). I would anticipate that CYP inhibition will be a bigger problem for azoles than azines and @edgriffen may have data for matched molecular pairs that enable this question to be addressed.
The S1 pocket which the heterocyclic rings occupy is set up to recognize rings with a single hydrogen bond (HB) acceptor (that interacts with the side chain of H163 that appears to be protonated). Additional aza nitrogens [nX2] will weaken the interacting HB acceptor while incurring a desolvation penalty. Indoles (e.g. ALP-POS-a3de0cb1-15) and indazoles (e.g. ALP-POS-a3de0cb1-16) effectively replace an HB acceptor [nX2] with an HB donor [nH] and this is unlikely to end well (is the idea to target the neutral form of the H163 sidechain?). I would be concerned about reactivity and ionization for amides (e.g. ALP-POS-a3de0cb1-1) derived from 1-aminobenzotriazoles.
Replacing a substituted nitrogen in a urea with carbon is likely to perturb conformational preferences. The Cambridge Structural Database (CSD) can be very useful for studying conformation preferences for scaffolds. GOLD, with which @RGlen may be familiar, and the OpenEye docking tools make it very easy to use knowledge gained from CSD when docking.
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Hi @alphalee @mc-robinson @JohnChodera @edgriffen @Joe
I’ve found five relevant benzotriazole structures ( CIQCEL | EVADEL | FOVVUI | HIRJEY | QAKZUZ ) in the Cambridge structural database that may be of interest. The relative orientations of carbonyl group and benzotriazole in these structures are similar to that observed for the ALP-POS-d2866bdf-1 ligand conformation (x10876). This suggests conformational locking (as discussed in this article) of the substructure is unlikely to lead to significant increases in potency (always worth checking though).
I’ll highlight some recent SAR from the 3-aminopyridine series in which an imidazopyridine is an order of magnitude less potent (in the fluorescence assay although RapidFire results are not yet available) than the isoquinoline from which it was derived. One rationale for this observation is that the isoquinoline accepts a hydrogen bond from the sidechain of H163 (contrary to my earlier comment, this appears to be neutral) with more optimal geometry than does the imidazopyridine. Given the similar binding modes, it may be worth investigating whether this SAR can be transferred from the 3-aminopyridine series to the benzotriazole series. My current view is that it will be easier to target the catalytic cysteine with a reversible warhead (e.g. nitrile) for the 3-aminopyridine series than for the benzotriazole series.
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