Virtual Screening for FDA-Approved Drugs That Selectively Inhibit Arginase Type 1 and 2

Arginases are often overexpressed in human diseases, and they are an important target for developing anti-aging and antineoplastic drugs. Arginase type 1 (ARG1) is a cytosolic enzyme, and arginase type 2 (ARG2) is a mitochondrial one. In this study, a dataset containing 2115-FDA-approved drug molecules is virtually screened for potential arginase binding using molecular docking against several ARG1 and ARG2 structures. The potential arginase ligands are classified into three categories: (1) Non-selective, (2) ARG1 selective, and (3) ARG2 selective. The evaluated potential arginase ligands are then compared with their clinical use. Remarkably, half of the top 30 potential drugs are used clinically to lower blood pressure and treat cancer, infection, kidney disease, and Parkinson's disease thus partially validating our virtual screen. Most notable are the antihypertensive drugs candesartan, irbesartan, indapamide, and amiloride, the antiemetic rolapitant, the anti-angina ivabradine, and the antidiabetic metformin which have minimal side effects. The partial validation also favors the idea that the other half of the top 30 potential drugs could be used in therapeutic settings. The three categories greatly expand the selectivity of arginase inhibition.

Automated summary

Arginases are overexpressed in human diseases, making them important targets for developing anti-aging and antineoplastic drugs. In this study, a virtual screening of 2115 FDA-approved drug molecules was conducted to identify potential arginase ligands. The results showed that half of the top 30 potential drugs are already used clinically for various conditions, validating the virtual screening approach. The three identified categories of potential arginase ligands greatly expand the selectivity of arginase inhibition.