Abstract
20α-hydroxysteroid dehydrogenase (AKR1C1) plays a key role in the metabolism of progesterone and other steroid hormones, thereby regulating their action at the pre-receptor level. AKR1C1 is implicated in neurological and psychiatric conditions such as catamenial epilepsy and depressive disorders. Increased activity of AKR1C1 is associated with termination of pregnancy and the development of breast cancer, endometriosis and endometrial cancer. Inhibition of the undesired activity of AKR1C1 will help reduce risks of premature birth, neurological disorders and the development of cancer. In order to identify potential leads for new inhibitors of AKR1C1 we adopted a virtual screening-based approach using the automated DOCK program. Approximately 250,000 compounds from the NCI database were screened for potential ligands based on their chemical complementarity and steric fit within the active site of AKR1C1. Kinetic analysis revealed 3,5-diiodosalicylic acid, an analogue of salicylic acid, as a potent competitive inhibitor with respect to the substrate 5β-pregnane-3α,20α-diol with a Ki of 9 nM. Aspirin, which is a well known salicylic acid-based drug, was also found to inhibit AKR1C1 activity. This is the first report to show aspirin (IC50=21 μM) and its metabolite salicylic acid (IC50=7.8 μM) as inhibitors of AKR1C1.
Keywords: Enzyme inhibitors, molecular docking, salicylic acid, 20α-hydroxysteroid dehydrogenase, aldo-keto reductase
Medicinal Chemistry
Title: A Salicylic Acid-Based Analogue Discovered from Virtual Screening as a Potent Inhibitor of Human 20α-Hydroxysteroid Dehydrogenase
Volume: 3 Issue: 6
Author(s): Urmi Dhagat, Vincenzo Carbone, Roland P.-T. Chung, Toshihiro Matsunaga, Satoshi Endo, Akira Hara and Ossama El-Kabbani
Affiliation:
Keywords: Enzyme inhibitors, molecular docking, salicylic acid, 20α-hydroxysteroid dehydrogenase, aldo-keto reductase
Abstract: 20α-hydroxysteroid dehydrogenase (AKR1C1) plays a key role in the metabolism of progesterone and other steroid hormones, thereby regulating their action at the pre-receptor level. AKR1C1 is implicated in neurological and psychiatric conditions such as catamenial epilepsy and depressive disorders. Increased activity of AKR1C1 is associated with termination of pregnancy and the development of breast cancer, endometriosis and endometrial cancer. Inhibition of the undesired activity of AKR1C1 will help reduce risks of premature birth, neurological disorders and the development of cancer. In order to identify potential leads for new inhibitors of AKR1C1 we adopted a virtual screening-based approach using the automated DOCK program. Approximately 250,000 compounds from the NCI database were screened for potential ligands based on their chemical complementarity and steric fit within the active site of AKR1C1. Kinetic analysis revealed 3,5-diiodosalicylic acid, an analogue of salicylic acid, as a potent competitive inhibitor with respect to the substrate 5β-pregnane-3α,20α-diol with a Ki of 9 nM. Aspirin, which is a well known salicylic acid-based drug, was also found to inhibit AKR1C1 activity. This is the first report to show aspirin (IC50=21 μM) and its metabolite salicylic acid (IC50=7.8 μM) as inhibitors of AKR1C1.
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Dhagat Urmi, Carbone Vincenzo, Chung P.-T. Roland, Matsunaga Toshihiro, Endo Satoshi, Hara Akira and El-Kabbani Ossama, A Salicylic Acid-Based Analogue Discovered from Virtual Screening as a Potent Inhibitor of Human 20α-Hydroxysteroid Dehydrogenase, Medicinal Chemistry 2007; 3 (6) . https://dx.doi.org/10.2174/157340607782360399
DOI https://dx.doi.org/10.2174/157340607782360399 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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