Halogen-Based 17β-HSD1 Inhibitors: Insights from DFT, Docking, and Molecular Dynamics Simulation Studies

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• High expression of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is linked to breast cancer and endometriosis.
• Hydroxyphenyl naphthol steroidomimetics are potential 17β-HSD1 inhibitors.
• Halogen-based drugs are increasingly approved, indicating their therapeutic potential.

Purpose of the Study:

• To design and evaluate novel halogen-substituted hydroxyphenyl naphthol steroidomimetics as 17β-HSD1 inhibitors.
• To investigate the structure-property relationships and binding interactions of these inhibitors with 17β-HSD1.
• To explore the potential of these compounds for treating estrogen-dependent disorders.

Main Methods:

• Synthesis of sixteen potential hydroxyphenyl naphthol steroidomimetics with halogen substitutions.
• Frontier Molecular Orbitals (FMO) analysis to assess electronic properties.
• Density Functional Theory (DFT) calculations for structure-property relationships.
• Molecular docking and molecular dynamics (MD) simulations to analyze binding interactions and stability.

Main Results:

• Halogen substitution, particularly tri-halogenation and iodine, significantly lowered the Lowest Unoccupied Molecular Orbital (LUMO) energy and reduced the HOMO-LUMO gap, indicating enhanced reactivity.
• Computed DFT descriptors correlated structure with binding ability to 17β-HSD1.
• Molecular docking revealed strong binding energies ranging from -10.26 to -11.94 kcal/mol.
• Molecular dynamics simulations confirmed the stability of the proposed compounds with 17β-HSD1.

Conclusions:

• Novel halogen-substituted hydroxyphenyl naphthol steroidomimetics are effective 17β-HSD1 inhibitors.
• These compounds exhibit favorable electronic properties, strong binding affinity, and good stability.
• The findings provide a basis for developing new therapeutic agents for estrogen-dependent diseases.