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

Arulsamy Kulandaisamy, Murugesan Panneerselvam, Rajadurai Vijay Solomon, Madhavan Jaccob, Jaganathan Ramakrishnan, Kumaradhas Poomani, Muralikannan Maruthamuthu, Nagendran Tharmalingam

    Research output: Contribution to journalArticlepeer-review

    6 Scopus citations

    Abstract

    The high expression of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) mRNA has been found in breast cancer tissues and endometriosis. The current research focuses on preparing a range of organic molecules as 17β-HSD1 inhibitors. Among them, the derivatives of hydroxyphenyl naphthol steroidomimetics are reported as one of the potential groups of inhibitors for treating estrogen-dependent disorders. Looking at the recent trends in drug design, many halogen-based drugs have been approved by the FDA in the last few years. Here, we propose sixteen potential hydroxyphenyl naphthol steroidomimetics-based inhibitors through halogen substitution. Our Frontier Molecular Orbitals (FMO) analysis reveals that the halogen atom significantly lowers the Lowest Unoccupied Molecular Orbital (LUMO) level, and iodine shows an excellent capability to reduce the LUMO in particular. Tri-halogen substitution shows more chemical reactivity via a reduced HOMO–LUMO gap. Furthermore, the computed DFT descriptors highlight the structure– property relationship towards their binding ability to the 17β-HSD1 protein. We analyze the nature of different noncovalent interactions between these molecules and the 17β-HSD1 using molecular docking analysis. The halogen-derived molecules showed binding energy ranging from −10.26 to −11.94 kcal/mol. Furthermore, the molecular dynamics (MD) simulations show that the newly proposed compounds provide good stability with 17β-HSD1. The information obtained from this investigation will advance our knowledge of the 17β-HSD1 inhibitors and offer clues to developing new 17β-HSD1 inhibitors for future applications.

    Original languageEnglish (US)
    Article number3962
    JournalMolecules
    Volume27
    Issue number12
    DOIs
    StatePublished - Jun 1 2022

    Keywords

    • 17β-HSD1 inhibitors
    • DFT
    • MD simulations
    • cancer
    • docking
    • estrogens
    • halogens
    • stability

    ASJC Scopus subject areas

    • Analytical Chemistry
    • Chemistry (miscellaneous)
    • Molecular Medicine
    • Pharmaceutical Science
    • Drug Discovery
    • Physical and Theoretical Chemistry
    • Organic Chemistry

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