VBY-825   Click here for help

GtoPdb Ligand ID: 10746

Synonyms: VBY825
Compound class: Synthetic organic
Comment: VBY-825 is a reversible cysteine protease inhibitor with high potency against cathepsins B, L, S and V [1]. Human cysteinyl cathepsins are required for proteolytic processing of virally encoded proteins during infection [2-3,5], including a likely requirement for proper processing of the SARS-CoV-2 S protein within the endosome (activating its fusogenic acitivity) [5]. Experimental evidence indicates that VBY-825 has some antiviral activity against SARS-CoV-2 [4]. In in vitro experiments VBY-825 inhibits SARS-CoV-2 entry. It does not inhibit the viral 3C-like protease (3CLpro) or papain-like protease (PLpro), which suggests that its antiviral activity is associated with inhibition of host proteases.

In the oncology setting, a pre-clinical model of pancreatic islet cancer revealed that VBY-825 exhibits significant anti-tumour activity.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 3
Rotatable bonds 16
Topological polar surface area 129.82
Molecular weight 535.18
XLogP 3.24
No. Lipinski's rules broken 1
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Canonical SMILES CC[C@@H](C(=O)C(=O)NC1CC1)NC(=O)[C@H](CS(=O)(=O)CC1CC1)N[C@H](C(F)(F)F)c1ccc(cc1)F
Isomeric SMILES CC[C@@H](C(=O)C(=O)NC1CC1)NC(=O)[C@H](CS(=O)(=O)CC1CC1)N[C@H](C(F)(F)F)c1ccc(cc1)F
InChI InChI=1S/C23H29F4N3O5S/c1-2-17(19(31)22(33)28-16-9-10-16)30-21(32)18(12-36(34,35)11-13-3-4-13)29-20(23(25,26)27)14-5-7-15(24)8-6-14/h5-8,13,16-18,20,29H,2-4,9-12H2,1H3,(H,28,33)(H,30,32)/t17-,18-,20-/m0/s1
Bioactivity Comments
VBY-825 impairs infection by SARS-CoV-2 in vitro with an EC50 of around 300 nM [4].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
cathepsin S Mm Inhibitor Inhibition 10.4 pKi - 1
pKi 10.4 (Ki 4x10-11 M) [1]
cathepsin S Hs Inhibitor Inhibition 9.9 pKi - 1
pKi 9.9 (Ki 1.3x10-10 M) [1]
cathepsin L Hs Inhibitor Inhibition 9.6 pKi - 1
pKi 9.6 (Ki 2.5x10-10 M) [1]
cathepsin V Hs Inhibitor Inhibition 9.6 pKi - 1
pKi 9.6 (Ki 2.5x10-10 M) [1]
cathepsin B Hs Inhibitor Inhibition 9.5 pKi - 1
pKi 9.5 (Ki 3.3x10-10 M) [1]
cathepsin S Rn Inhibitor Inhibition 9.1 pKi - 1
pKi 9.1 (Ki 7.7x10-10 M) [1]
cathepsin F Hs Inhibitor Inhibition 8.3 pKi - 1
pKi 8.3 (Ki 4.7x10-9 M) [1]