Piperazine-thiophene hybrid as a promising SGLT2 inhibitor: insights from DFT and molecular docking studies

The compound 1-(piperazin-1-yl)-2-(thiophen-2-yl) ethan-1-one (PT) was comprehensively investigated through computational and molecular docking approaches to evaluate its structural, electronic, and pharmacological properties. Density functional theory (DFT) calculations at the B3LYP/cc-pVDZ level were employed to optimize molecular geometry and analyze electronic descriptors, including frontier molecular orbitals (FMOs), global reactivity parameters, and dipole moments in both gas and solvent phases. PT demonstrated moderate chemical stability, high nucleophilicity, and low electrophilicity, suggesting potential for biological activity. Non-linear optical (NLO) properties and UV-spectra computed via time-dependent DFT (TD-DFT) revealed strong solvent dependence and enhanced polarizability, particularly in polar environments. Molecular electrostatic potential (MEP), electron localization function (ELF), and localized orbital locator (LOL) analyses provided deeper insights into reactive sites and electron distribution. Furthermore, natural population analysis (NPA), Mulliken charge distribution, and natural bond orbital (NBO) analyses confirmed intramolecular charge delocalization and stabilizing donor-acceptor interactions. Finally, molecular docking simulations revealed favorable binding of PT to the human SGLT2-MAP17 protein complex (PDB ID: 8HEZ), with a binding energy of -6.93 kcal/mol and multiple stabilizing noncovalent interactions. These findings suggest that PT could serve as a promising lead compound for SGLT2 inhibition and warrant further pharmacological evaluation.

Journal

STRUCTURAL CHEMISTRY

Year

2025

ISSN

1040-0400

eISSN

1572-9001

DOI

10.1007/s11224-025-02555-x

WoS UID

WOS:001522680100001

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