A salicylic acid-based analogue discovered from virtual screening as a potent inhibitor of human 20alpha-hydroxysteroid dehydrogenase

Dhagat U, Urmi Dhagat, Carbone V, Vincenzo Carbone, Roland P-T Chung, Chung RP, Matsunaga T, Toshihiro Matsunaga, Satoshi Endo, Endo S, Hara A, Akira Hara, Ossama El-Kabbani, El-Kabbani O
Medicinal chemistry (Shariqah (United Arab Emirates)) · 2007 · doi:10.2174/157340607782360399 · PMID:18045204
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Virtual screening identified 3,5-diiodosalicylic acid as a potent inhibitor of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1), and aspirin and salicylic acid also demonstrated inhibitory activity.

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This study utilized virtual screening of approximately 250,000 compounds to identify potent inhibitors of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1), an enzyme involved in steroid hormone metabolism. Kinetic analysis identified 3,5-diiodosalicylic acid as a highly effective competitive inhibitor with a Ki of 9 nM, while also demonstrating that aspirin and its metabolite salicylic acid possess inhibitory activity against the enzyme. The research highlights these salicylic acid-based analogues as potential leads for modulating AKR1C1 activity to mitigate associated pathological conditions. Relevance to endometriosis: listed as one indication for AKR1C1 inhibition, though the paper's main focus is on the biochemical characterization of enzyme inhibitors rather than clinical treatment of the disease.

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Abstract

20alpha-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 5beta-pregnane-3alpha,20alpha-diol with a K(i) 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 (IC(50)=21 microM) and its metabolite salicylic acid (IC(50)=7.8 microM) as inhibitors of AKR1C1.
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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 9

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Condition tags

endometriosis

MeSH descriptors

20-Hydroxysteroid Dehydrogenases Computer Simulation Drug Evaluation, Preclinical Enzyme Inhibitors Salicylic Acid 20-Hydroxysteroid Dehydrogenases Binding Sites Databases, Factual Drug Evaluation, Preclinical Enzyme Inhibitors Enzyme Inhibitors Humans Inhibitory Concentration 50 Ligands Protein Binding Salicylic Acid

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