Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π‐Stacking Interactions and Chalcogen Bonding in the S3 Pocket

Abstract

We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarene⋅⋅⋅peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (K ) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (K =4 nm) and benzothiazolyl (K =17 nm) ligands was enhanced by intermolecular C-S⋅⋅⋅O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

“…This work provides an important roadmap for developing improved chemical biology tools where a halogen-protein interaction has successfully been utilized [97]. To examine what effect amide···heteroarene π-stacking interactions may have on chalcogen bonding in the S3 pocket of cathepsin L, Giroud et al utilized triazine-nitrile scaffold [145]. The authors synthesized a diverse set of triazine-nitrile compounds with a diversified heteroarenes targeting S3 pocket; the S1 and S2 substituents were kept constant.…”

“…Their study demonstrated the importance of both intermolecular interactions and conformational strain in assessing the effect of heterobicyclic ligands at the S3 pocket that could be potentially be utilized to develop cathepsin L selective inhibitors. To examine what effect amide···heteroarene π-stacking interactions may have on chalcogen bonding in the S3 pocket of cathepsin L, Giroud et al utilized triazine-nitrile scaffold [145]. The authors synthesized a diverse set of triazine-nitrile compounds with a diversified heteroarenes targeting S3 pocket; the S1 and S2 substituents were kept constant.…”

“…Much excitement remains as new cathepsin L functions continue to emerge from specific cell types in the coming years. 4AXL X-ray 1.92 [190] 4AXM X-ray 2.80 [190] 5F02 X-ray 1.43 [191] 5I4H X-ray 1.42 [192] 5MAE X-ray 1.00 [145] 5MAJ X-ray 1.00 [145] 5MQY X-ray 1.13 [123] 6EZP X-ray 1.37 [98] 6EZX X-ray 2.34 [98] 6F06 X-ray 2.02 [98] Funding: S.K.P. gratefully acknowledges the financial support from the National Science Foundation (NSF); Grant no.…”

Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs

“…The gain in Gibbsp rotein-ligand binding energyb ecomes enhanced with increasing degree of preorganizationo ft he ligand;i no ther words, the preferred conformations of bounda nd unboundl igandss hould be similar. [1,9] While the energeticso ft he conformationso ff ree and bound ligand can be evaluated by computational methods, [5,10] conformational preferences of small molecules are best extractedf rom searches in the Cambridge StructuralD atabase (CSD), [11][12][13][14] reaching more than 875 000 entries in 2017. [6,7] Some reports suggest to set the threshold for the bioactive conformation at 3kcal mol À1 of the loweste nergy conformation, [6,8] whereas others give am aximum Gibbs energy differenceo f5kcal mol À1 .…”

Lithiation of 2-bromo-4-(1,3-dioxolan-2-yl)-1,3-thiazole

“…1,3-Thiazole derivatives exhibit the activities of selective enzyme inhibitors, [1][2][3][4] sigma receptors, 5,6 adenosine receptors 7,8 antagonists, and new T-type calcium channel blockers. 9 The actual task today is to obtain polyfunctional 1,3-thiazoles, which are suitable for further modification in order to synthesize the libraries of thiazole derivatives for screening and searching for pharmacologically promising compounds.…”