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Cited by 37Computational Drug Discovery MethodsSteroid Chemistry and BiochemistryProtein Structure and Dynamics

Molecular docking simulations of steroid substrates into human cytosolic hydroxysteroid dehydrogenases (AKR1C1 and AKR1C2): insights into positional and stereochemical preferences

Jin, Yi, Penning, Trevor M.·2006·Steroids
DOI 10.1016/j.steroids.2005.12.002
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Abstract

AKR1C1 and AKR1C2 are human cytosolic hydroxysteroid dehydrogenases, which play pivotal roles in the metabolism and action of natural and synthetic steroid hormones. The two enzymes are highly homologous, and have distinct positional and stereochemical preferences with various substrates. We performed molecular docking simulations of three steroid substrates, including an androgen (5alpha-dihydrotestosterone, DHT), a progestin (progesterone, PRO), and a synthetic hormone ([7alpha,17alpha]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one or tibolone, TIB), into the active sites of the two enzymes. For each substrate and enzyme pair, the activity inferred by the "productive" docking models (in which the spatial arrangement of the steroid and the cofactor would permit a reaction) matched the experimentally observed positional and stereochemical outcome. These productive conformations were energetically and statistically favored except for TIB and PRO with AKR1C2, where experimentally strong substrate inhibition and low activity were observed, respectively. Results showed that (i) a 3-ketosteroid (DHT) and a 20-ketosteroid (PRO) were reduced by AKR1C1 since the carbonyl groups could occupy the same position by "backwards" binding of steroids; (ii) 3alpha-reduced (DHT) and 3beta-reduced (TIB) products were formed by AKR1C2 since the angular methyl groups of the steroids were inverted by "upside-down" binding of steroids; and (iii) the 3beta- and 3alpha-reduction of DHT by AKR1C1 and AKR1C2, respectively occurred since the steroids employed a "swinging" motion to present opposite faces to the cofactor. Favorable nonproductive modes were observed with all substrates in both enzymes in which the steroid was bound at a "near-entry" position and/or an "in-middle" position, which may influence the reaction coordinate.

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  • Hydroxysteroid product stereochemistry can be inverted by the ketosteroid being pushed across the pocket or bound upside down.

    “stereochemistry of the hydroxysteroid product can be inverted by either the ketosteroid being pushed across the steroid pocket by steric forces or the ketosteroid can be bound upside down”

    From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [19]

  • Ketosteroid substrates can bind in reverse orientation, with the D-ring at the base of the pocket instead of the A-ring.

    “ketosteroid substrates can bind in reverse orientation so that the D-ring binds at the base of the pocket instead of the A-ring”

    From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [19]

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Authors
Jin, Y., & Penning, T. M.
Affiliations
University of Pennsylvania (US)
Corresponding author
Penning, Trevor M.
ORCID
Penning, Trevor M.
Venue
Steroids
Publisher
Elsevier BV
Published
2006-05
Volume
71
Issue
5
Pages
380-391
ISSN
0039-128X (ISSN-L)
DOI
10.1016/j.steroids.2005.12.002
OpenAlex
W2159615011
Cited by
37
References
28
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2022: 2 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 2 · 2016: 3 · 2014: 4 · 2013: 1 · 2012: 3
FWCI
2.45
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Steroids (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-47015, R01DK047015)
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
AKR1C1, AKR1C2, dihydrotestosterone, progesterone, tibolone, steroid dose reduction, substrate inhibition
MeSH terms
Binding Sites, Computer Simulation, Humans, Hydroxysteroid Dehydrogenases, Models, Chemical, Models, Molecular, Molecular Conformation, Protein Binding, Stereoisomerism, Steroids, Structure-Activity Relationship, 20-Hydroxysteroid Dehydrogenases, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)

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