Update on inhibitors of 17β-hydroxysteroid dehydrogenase type 1: Reports on structure-function relationship, docking and molecular dynamic simulations

Martinović, Manuel; Sedlacek Miskerikova, Marketa; Novak, Jurica; Rižner, Tea Lanišnik (2026) Update on inhibitors of 17β-hydroxysteroid dehydrogenase type 1: Reports on structure-function relationship, docking and molecular dynamic simulations. European Journal of Medicinal Chemistry, 316 . ISSN 0223-5234

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Official URL: http://doi.org/10.1016/j.ejmech.2026.118999

Abstract

17-Hydroxysteroid dehydrogenase type 1 (HSD17B1) is a crucial enzyme in the family of 17-hydroxysteroid dehydrogenases, serving as one of the primary activators of estrogens. Its physiological significance is highlighted by its involvement in a wide range of estrogen-related conditions, including benign diseases and hormone-dependent cancers. Consequently, the development of selective inhibitors for HSD17B1 has attracted sustained interest for several decades. Numerous lead compounds have been identified, and various strategies for reversible inhibition have been explored, reflecting the complexity of modulating estrogen biosynthesis without causing unwanted side effects. This review focuses on advances made since 2018, highlighting how research has continued to refine existing leads by improving potency, enhancing metabolic stability, and minimising estrogenic activity. In addition to optimising known scaffolds, novel directions have emerged, such as designing compounds capable of dual targeting across different enzymes involved in estrogen formation and introducing new structural scaffolds. The inhibitor candidates identified in recent years can be grouped into five distinct subcategories, each representing a different approach to reversible HSD17B1 inhibition. To provide a comparative perspective, representative compounds from these categories have been evaluated using molecular dynamics simulations, offering insight into binding behaviour and mechanistic differences.

Item Type:

Article

Uncontrolled Keywords:

17β-hydroxysteroid dehydrogenase type 1; HSD17B1; Breast cancer; Molecular dynamics; Inhibitors

Subjects:

NATURAL SCIENCES > Chemistry
BIOMEDICINE AND HEALTHCARE > Pharmacy

Divisions:

Center for Informatics and Computing
Division of Physical Chemistry

Projects: