Computational design of substrate selective inhibition

• DOI: 10.1371/journal.pcbi.1007713
• Publication Date: 2020-03-20T17:55:46Z
• Authors: Benny Da’adoosh; Kon Kaito; Keishi Miyashita; Minoru Sakaguchi; Amiram Goldblum
• Keywords: Oligopeptidase

Most enzymes act on more than a single substrate. There is frequently need to block the production of pathogenic outcome enzymatic activity substrate but avoid blocking others its catalytic actions. Full might cause severe side effects because some products that catalysis may be vital. Substrate selectivity required not possible achieve by residues an enzyme. That basis for "Substrate Selective Inhibitors" (SSI), and there are several molecules characterized as SSI. However, none have yet been designed or discovered computational methods. We demonstrate approach discovery Inhibitors one enzyme, Prolyl Oligopeptidase (POP) (E.C 3.4.21.26), serine protease which cleaves small peptides between Pro other amino acids. Among those Thyrotropin Releasing Hormone (TRH) Angiotensin-III (Ang-III), differing in both their binding (Km) turnover (kcat). used our in-house "Iterative Stochastic Elimination" (ISE) algorithm structure-based "Pharmacophore" construct two models identifying SSI POP. A dataset ~1.8 million commercially available was initially reduced less 12,000 were screened these final set 20 sent experimental validation (five random tested comparison). Two out 20, with high score ISE model, successful pharmacophore confirmed vitro measurements. One competitive inhibitor Ang-III (increases Km), non-competitive towards TRH (decreases Vmax).