Design, Synthesis, and Evaluation of Nonpeptidic Inhibitors of Human Rhinovirus 3C Protease

• DOI: 10.1021/jm960603e
• Publication Date: 2002-07-26T05:03:09Z
• Authors: Stephen E. Webber; Jayashree Tikhe; Stephen T. Worland; Shella A. Fuhrman; Thomas F. Hendric...; David A. Matthews; Robert A. Love; Amy K. Patick; James W. Meador; Rose Ann Ferre; Edward L. Brown; Dorothy M. DeLisle; Clifford E. Ford; Susan L. Binford
• Keywords: Rhinovirus; Isatin; Cysteine protease; Cocrystal

The design, synthesis, and biological evaluation of reversible, nonpeptidic inhibitors human rhinovirus (HRV) 3C protease (3CP) are reported. A novel series 2,3-dioxindoles (isatins) were designed that utilized a combination protein structure-based drug molecular modeling, structure-activity relationship (SAR). C-2 carbonyl isatin was envisioned to react in the active site HRV 3CP with cysteine responsible for catalytic proteolysis, thus forming stabilized transition state mimic. Molecular-modeling experiments using apo crystal structure rhinovirus-serotype 14 (HRV-14) peptide substrate model allowed us design recognition features into P1 P2 subsites, respectively, from 5- 1-positions isatin. Attempts optimize properties subsite SAR at 5-position performed. In addition, ab initio calculations carried out on several 5-substituted isatins investigate stability sulfide adducts C-3. prepared by general synthetic methods, starting commercially available nearly every case. All compounds tested inhibition purified HRV-14 3CP. Compounds 8, 14, 19 found have excellent selectivity compared other proteolytic enzymes, including chymotrypsin cathepsin B. Selected assayed antiviral activity against HRV-14-infected HI-HeLa cells. 2.8 cocrystal derivative covalently bound 2 (HRV-2) solved revealed situated essentially same conformation as modeled.