@article {Shah34, author = {Parag P. Shah and Michael C. Myers and Mary Pat Beavers and Jeremy E. Purvis and Huiyan Jing and Heather J. Grieser and Elizabeth R. Sharlow and Andrew D. Napper and Donna M. Huryn and Barry S. Cooperman and Amos B. Smith III and Scott L. Diamond}, title = {Kinetic Characterization and Molecular Docking of a Novel, Potent, and Selective Slow-Binding Inhibitor of Human Cathepsin L}, volume = {74}, number = {1}, pages = {34--41}, year = {2008}, doi = {10.1124/mol.108.046219}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {A novel small molecule thiocarbazate (PubChem SID 26681509), a potent inhibitor of human cathepsin L (EC 3.4.22.15) with an IC50 of 56 nM, was developed after a 57,821-compound screen of the National Institutes of Health Molecular Libraries Small Molecule Repository. After a 4-h preincubation with cathepsin L, this compound became even more potent, demonstrating an IC50 of 1.0 nM. The thiocarbazate was determined to be a slow-binding and slowly reversible competitive inhibitor. Through a transient kinetic analysis for single-step reversibility, inhibition rate constants were kon = 24,000 M-1s-1 and koff = 2.2 {\texttimes} 10-5 s-1 (Ki = 0.89 nM). Molecular docking studies were undertaken using the experimentally derived X-ray crystal structure of papain/CLIK-148 (1cvz. pdb). These studies revealed critical hydrogen bonding patterns of the thiocarbazate with key active site residues in papain. The thiocarbazate displayed 7- to 151-fold greater selectivity toward cathepsin L than papain and cathepsins B, K, V, and S with no activity against cathepsin G. The inhibitor demonstrated a lack of toxicity in human aortic endothelial cells and zebrafish. In addition, the thiocarbazate inhibited in vitro propagation of malaria parasite Plasmodium falciparum with an IC50 of 15.4 μM and inhibited Leishmania major with an IC50 of 12.5 μM. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/74/1/34}, eprint = {https://molpharm.aspetjournals.org/content/74/1/34.full.pdf}, journal = {Molecular Pharmacology} }