Abstract
Cortisol synthase (CYP11B1) is the main enzyme for the endogenous synthesis of cortisol and its inhibition is a potential way for the treatment of diseases associated with increased cortisol levels, such as Cushing's syndrome, metabolic diseases, and delayed wound healing. Aldosterone synthase (CYP11B2) is the key enzyme for aldosterone biosynthesis and its inhibition is a promising approach for the treatment of congestive heart failure, cardiac fibrosis, and certain forms of hypertension. Both CYP11B1 and CYP11B2 are structurally very similar and expressed in the adrenal cortex. To facilitate the identification of novel inhibitors of these enzymes, ligand-based pharmacophore models of CYP11B1 and CYP11B2 inhibition were developed. A virtual screening of the SPECS database was performed with our pharmacophore queries. Biological evaluation of the selected hits lead to the discovery of three potent novel inhibitors of both CYP11B1 and CYP11B2 in the submicromolar range (compounds 8–10), one selective CYP11B1 inhibitor (Compound 11, IC50 = 2.5 μM), and one selective CYP11B2 inhibitor (compound 12, IC50 = 1.1 μM), respectively. The overall success rate of this prospective virtual screening experiment is 20.8% indicating good predictive power of the pharmacophore models.
Highlights
Cortisol is a glucocorticoid hormone that modulates many processes in the body such as blood sugar levels, immune system activity, metabolism of proteins, carbohydrates and fats, and bone formation (Cain and Cidlowski, 2017)
Pharmacophore models for cytochrome p450 11B1 (CYP11B1) and cytochrome p450 11B2 (CYP11B2) inhibitors were derived from highly potent training compounds
This pharmacophore model was composed of two aromatic ring features (AR-1 and AR-2), three hydrophobic features (H1, H-2, and H-3), three hydrogen bond acceptors (HBA-1, HBA-2, and HBA-3), and 47 exclusion volume (XVOL) (Figures 3B,C)
Summary
Cortisol is a glucocorticoid hormone that modulates many processes in the body such as blood sugar levels, immune system activity, metabolism of proteins, carbohydrates and fats, and bone formation (Cain and Cidlowski, 2017). The use of glucocorticoid receptor antagonists for treating this situation often comes with an increased secretion of cortisol, potentially due to the pituitary feedback mechanism (Orth, 1978). An alternative treatment could be the reduction of cortisol formation by inhibiting cytochrome P450 11B1 It catalyzes the final step in the formation of cortisol by hydroxylating 11deoxycortisol in the zona fasciculate of adrenal cortex (Figure 1) (Sayers, 1950). This mechanism of action is expected not to cause the adverse effects observed for glucocorticoid receptor antagonists (Nieman, 2002)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
