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StructuralGenomicsConsortium / CNP7-RdRp-S1-Tetrazole

An Open Chemistry Networks Project Targeting SARS-CoV-2 RdRp
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The commercially-available analogues of the original hit RA-0010017-01 #2

Open HadiaAmahli opened 1 year ago

HadiaAmahli commented 1 year ago

We are interested in exploring the potency of the original hit RA-0010017-01 analogues to study the SAR which will help to make a potent drug-like molecule. Here are the commercially available analogues: Image 1

We are also interested in the SAR study of the carboxylic acid isosteres of tetrazol as well, however these analogues are not commercially available (see below): image 2

HadiaAmahli commented 1 year ago

Here are the commercial analogues shipped from Chemspace & Molport and to be tested in the UNC for their antiviral activity vs SARS-COV2 RdRp.

Github 2 <html xmlns:v="urn:schemas-microsoft-com:vml" xmlns:o="urn:schemas-microsoft-com:office:office" xmlns:x="urn:schemas-microsoft-com:office:excel" xmlns="http://www.w3.org/TR/REC-html40">

Formula | MW | Purity | Salt_Name | Salt_ratio | MW_salt | Smile | Chemical name -- | -- | -- | -- | -- | -- | -- | -- C20H15N5O2 | 357.3654 | 100 |   |   | 0 | O=C(NC=1C=CC=C(OC=2C=CC=CC2)C1)C=3C=CC(=CC3)C4=NN=NN4 | N-(3-phenoxyphenyl)-4-(1H-1,2,3,4-tetrazol-5-yl)benzamide C21H17N5O2 | 371.392 | 100 |   |   | 0 | CC=1C=CC=C(OC=2C=CC(NC(=O)C=3C=CC(=CC3)C4=NN=NN4)=CC2)C1 | N-[4-(3-methylphenoxy)phenyl]-4-(1H-1,2,3,4-tetrazol-5-yl)benzamide C21H17N5O2 | 371.392 | 100 |   |   | 0 | CC=1C=CC(OC=2C=CC(NC(=O)C=3C=CC(=CC3)C4=NN=NN4)=CC2)=CC1 | N-[4-(4-methylphenoxy)phenyl]-4-(1H-1,2,3,4-tetrazol-5-yl)benzamide C21H15N3O2S | 373.4277 | 91 |   |   | 0 | O=C(NC=1C=CC(=CC1)C2=CSN=N2)C=3C=CC(OC=4C=CC=CC4)=CC3 | 4-phenoxy-N-[4-(1,2,3-thiadiazol-4-yl)phenyl]benzamide C20H15N5O3 | 373.3648 | 100 |   |   | 0 | OC=1C=CC(OC=2C=CC=C(C2)C(=O)NC=3C=CC=C(C3)C4=NN=NN4)=CC1 | 3-(4-hydroxyphenoxy)-N-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]benzamide C19H14ClN5O3S | 427.8642 | 100 |   |   | 0 | ClC=1C=CC=C(OC=2C=CC(=CC2)S(=O)(=O)NC=3C=CC(=CC3)C4=NN=NN4)C1 | 4-(3-chlorophenoxy)-N-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]benzene-1-sulfonamide C20H15N5O2 | 357.3654 | 100 |   |   | 0 | O=C(NC=1C=CC(OC=2C=CC=CC2)=CC1)C=3C=CC(=CC3)C4=NN=NN4 | N-(4-phenoxyphenyl)-4-(1H-1,2,3,4-tetrazol-5-yl)benzamide C21H15BrN4O2 | 435.2734 | 100 |   |   | 0 | BrC=1C=CC=C(OC=2C=CC(=CN2)C(=O)NC=3C=CC(=CC3)C4=NC=CN4)C1 | 6-(3-bromophenoxy)-N-[4-(1H-imidazol-2-yl)phenyl]pyridine-3-carboxamide C19H20F3N5O5 | 455.3878 | 100 | trifluoroacetic acid | 1 | 114.0233 | CC=1C=CC2=NC(CN3CCCC4(C3)NC(=O)NC4=O)=CC(=O)N2C1.OC(=O)C(F)(F)F | 7-({7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}methyl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; trifluoroacetic acid C19H20F3N5O5 | 455.3878 | 100 | trifluoroacetic acid | 1 | 114.0233 | CC1=CC=CC2=NC(CN3CCCC4(C3)NC(=O)NC4=O)=CC(=O)N12.OC(=O)C(F)(F)F | 7-({6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}methyl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; trifluoroacetic acid C19H20F3N5O5 | 455.3878 | 98 | trifluoroacetic acid | 1 | 114.0233 | CC1=CC=CN2C(=O)C=C(CN3CCCC4(C3)NC(=O)NC4=O)N=C12.OC(=O)C(F)(F)F | 7-({9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}methyl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; trifluoroacetic acid C23H18N2O2 | 354.409 | 90 |   |   |   | O=C(C1=CC=C(N2C=CC=C2)C=C1)NC3=CC=C(C=C3)OC4=CC=CC=C4 | N-(4-phenoxyphenyl)-4-(1H-pyrrol-1-yl)benzamide C25H19N3O2 | 393.446 | 90 |   |   |   | O=C(C1=CC=C(OC2=CC=CC=C2)C=C1)NC3=CC=C(/N=N/C4=CC=CC=C4)C=C3 | 4-phenoxy-N-{4-[(1E)-2-phenyldiazen-1-yl]phenyl}benzamide

mattodd commented 1 year ago

Great @HadiaAmahli. Could you please post the SMILES and InChi into a comment below? This means it's easier for machines to find these molecules. If these molecules already have RA numbers, you could include those too.

HadiaAmahli commented 1 year ago

Here are the purchased and synthetic compounds shipped to the UNC to test their activity vis SARS-CoV-2 RdRp by Jim Sacchettini: Final-Shipped products to UNC-SARS-CoV-2 RdRp.xlsx Three of the purchased analogues (highlighted in orange) showed IC50< 20 μM (11.78, 15.05 and 17.53 μM).The target molecule vis SARS-Cov-2 RdRp: RA-0010017-2 showed (IC50= 3.96 μM). RdRp-TEST.xlsx All these results are pending for Gel-based & solubility screening (will get data by next week) as Ken’s lab at UNC will be running a picogreen assay and Jim will run triplicate to get a better understanding about the compounds’ activity.

HadiaAmahli commented 11 months ago

The Gel-based screening and h-mtRNAP assay data showed that the compounds mentioned above were active particularly RA-0002723-01 which showed 100% inhibition activity vis RdRp at 100 uM. RA-0010017 Series (1).pptx. The latest solubility data for the compounds exhibited activity as mentioned in the last issue, showed poor solubility as well as poor permeability that's why we are not going further with these analogs and we are prioritizing new hits showed better activity and selectivity.
CLND Solubility Results_20230928 UNC_Analiza Solubility Sample Submission Form_Hadia.xlsx PAMPA Results_20230928 Analiza Sample Submission_UNC_ADME_Hadia.xlsx

HadiaAmahli commented 9 months ago

The latest data showed that the most active analogue RA-0002723 image - The analogue of the original hit RA-0010017 showed IC50= 14 uM image with selectivity IC50= uM Micromolar image. This activity is far away from the original hit activity RA-0010017 (IC50= 3uM) regarding Jim's Picogreen assay, the MW of this analogue RA-0002723 is ~428 g/mol so the LE ligand efficiency is very low.

HadiaAmahli commented 9 months ago

All the attempts to decrease MW were inactive. A few analogues showed activity in gel based RdRp, however they were active on hmt-RNAP. No signal for selectivity. The only thing we should try here is how to increase potency or ligand efficiency of RA-0002723

HadiaAmahli commented 8 months ago

On 24th Jan 2024, all the purchased analogues of the original hit RA-0010017-01 were subjected to the intercalator assay to test their binding to the RNA, using Ethidium Bromide as a positive control binding to RNA at both concentration 1 uM and 4 uM and 449C which is a small molecule used as negative control showing no binding. All the analogues of RA-0010017-02 showed no binding or very low binding at 12.5uM, and two of them showed binding at 50uM which are: RA-0002721 and RA-0002740

image

You can find this data here

mattodd commented 8 months ago

So the implication of these data is that the binding that is observed is to protein and not to the nucleic acid that is in the assay?

HadiaAmahli commented 8 months ago

So the implication of these data is that the binding that is observed is to protein and not to the nucleic acid that is in the assay?

Yes that's correct, these data prove that although these analogues are planar (Multi aromatic rings compounds) but they don't intercalate with the RNA of the protein. Their affinity/binding activity observed is a result of the binding interaction with the target protein SARS-CoV-2 RdRp itself not with the RNA.

rahmanszsaleem commented 7 months ago

These are interesting compounds. @HadiaAmahli do we have the aggregation data available for these compounds? Considering the paper below image, I think we should be looking forward to the data at this stage.

HadiaAmahli commented 7 months ago

Rahman, could you please copy the link of the paper you mentioned as a link not as an image please to be able to check it. Thank you

rahmanszsaleem commented 7 months ago

https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01105

HadiaAmahli commented 7 months ago

https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01105

Rahman, thank you for sending this paper, however we used to check all our molecules on the same aggregator advisor in READDI-AVIDD project : (https://advisor.bkslab.org/) and this type of molecules are likely to be aggregated but we are still waiting for the aggregation assay data to confirm.