Abstract
Protein Arginine Deiminase type 4 (PAD4) is a new therapeutic target for the treatment of rheumatoid arthritis. In this study, ligand-based virtual screening with the integration with drug repurposing strategy was applied to the discovery of PAD4 inhibitors. Ultrafast Shape Recognition (USR) was used to search for compounds with similar shape to a previously reported inhibitor with harmful side-effects, i.e., streptonigrin. Thirty five lead-like compounds and two existing drugs were obtained from virtual screening and their inhibitory activity was tested at fixed concentration of 100 μM. Five lead-like compounds showed significant inhibition on the enzymatic activity of PAD4. The potency of the best compound was investigated by carrying out IC50 study. Importantly, the structure of the best of these new active molecules was strikingly different from that of streptonigrin. Furthermore, this new PAD4 inhibitor is the most potent to date found by a computational approach and its structure can be optimized in the future for the design of an even better inhibitor of PAD4.
Highlights
Protein arginine deiminase, known as Peptidyl Arginine Deiminase (PAD) is an enzyme catalyzing post translation conversion of arginine to citrulline
After Ultrafast Shape Recognition (USR) highlighted a number of compounds as hits, a quick experimental screening was carried out to identify the inhibitory activity of the compounds
A moderately potent inhibitor for Protein Arginine Deiminase Type 4 (PAD4) has been discovered through ligand-based virtual screening with the application of USR for molecular shape similarity search
Summary
Known as Peptidyl Arginine Deiminase (PAD) is an enzyme catalyzing post translation conversion of arginine to citrulline. It is a Ca2+ dependent enzyme; without Ca2+, it cannot perform the conversion properly due to improper structural rearrangements for substrate binding [1]. There are five isoforms of human PADs, which are PAD1 to PAD4 and PAD6. Each isoform has their own physiological roles in different locations in human body. One of its physiological roles in human and other mammal’s bodies is cellular differentiation. While PAD1 and PAD3 are playing role in skin differentiation, PAD2 has putative role in brain development and PAD6 is important in embryonic development [2]
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