Computational Repositioning and Experimental Validation of Approved Drugs for HIF-Prolyl Hydroxylase Inhibition

• Published in: Journal of chemical information and modeling Vol. 53; no. 7; pp. 1818 - 1824
• Main Authors: Teli, Mahesh Kumar, G. K, Rajanikant
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 22.07.2013
• Subjects: Biological and medical sciences; Chemistry; Drug Approval; Enzyme Inhibitors - pharmacology; Enzymes; Exact sciences and technology; FDA approval; General and physical chemistry; General pharmacology; General. Nomenclature, chemical documentation, computer chemistry; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors; Hypoxia-Inducible Factor-Proline Dioxygenases - chemistry; Medical sciences; Models, Molecular; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Prescription drugs; Protein Conformation; R&D; Research & development; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry; Drug; Validation; Stability; Disordered system; Pharmaceutical technology; Pipeline processor; Virtual screening; Activation; Inflammation; Pharmacology; Medical screening; Experimental study; Adaptive method; Computational chemistry; Design process; Ischemia; Inhibition
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci400254a

HIF stability and activation are governed by a family of dioxygenases called HIF prolyl-4-hydroxylases (PHDs). It has been identified as a new target to augment the adaptive machinery that governs cytoprotection in disorders associated with ischemia/reperfusion, inflammation, and oxidative stress. In this sense, PHD inhibition has been proposed to mimic, at least in part, the protective effects of exposure to hypoxia. Exploiting drug polypharmacology to identify novel modes of actions for drug repurposing has gained significant attention in the current era of weak drug pipelines. The present work plan aims at giving new purpose to some well-established FDA-approved drugs. Here, we propose that by combining the literature survey, docking, and manual interpretation altogether, we were able to perform virtual screening on FDA-approved drugs to identify potential PHD inhibitors. Upon screening of 1537 marketed drugs, a final set of six hits were selected for experimental testing. All six drugs were divers, and immuno blotting was carried out to evaluate their ability to upregulate HIF in order to validate our hypothesis. Out of the six, three drugs showed significant upregulation of HIF possibly by inhibiting the PHD. It is believed that the appropriate use of the literature survey, docking, manual interpretation, and experimental validation strategy in the drug design process should improve the ability to identify hits and confirm their potential to serve as basis for drug repurposing.