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<p>A comprehensive theoretical investigation was carried out on two antihypertensive drugs, Hydrochlorothiazide (HCTZ) and Hydroflumethiazide (HFTZ), using Density Functional Theory (DFT) with the B3LYP-D3(BJ)/6-311++ G(d,p) hybrid functional including dispersion corrections.Hirshfeld surface analysis and fingerprint plots quantified intra- and intermolecular interactions, while the electron localization function (ELF) revealed atomic shell structures and localized lone pairs, especially around electronegative centers. Molecular docking studies highlighted significant binding interactions of both drugs with the OSR1 kinase protein, with HFTZ exhibiting superior inhibitory potential. Molecular dynamics simulations further confirmed the structural stability and interaction profiles of both drugs within the active site. HCTZ demonstrated a consistent interaction with GLY520, while HFTZ exhibited adaptive binding to the flexible loop regions, especially interacting with LEU473 through its sulfonamide group. These findings provide deep insights into the structural, electronic, and binding characteristics of these antihypertensive agents, supporting their pharmacological relevance and guiding future drug design strategies. This comparative framework highlights how subtle structural variations, such as fluorine substitution in HFTZ, influence electronic delocalization and binding behaviour.</p> Graphical abstract <p></p>

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Theoretical insights into the reactivity, topological properties, and OSR1 kinase interaction of anti-hypertensive drugs: a DFT and docking-based study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月3日

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  • Niranjana Devi Rajendran,
  • Arulraj Ramalingam,
  • Justin Prabakaran,
  • Ronaldo Anuf,
  • Srinivas Ganjipete,
  • Parasuraman Pavadai

摘要

A comprehensive theoretical investigation was carried out on two antihypertensive drugs, Hydrochlorothiazide (HCTZ) and Hydroflumethiazide (HFTZ), using Density Functional Theory (DFT) with the B3LYP-D3(BJ)/6-311++ G(d,p) hybrid functional including dispersion corrections.Hirshfeld surface analysis and fingerprint plots quantified intra- and intermolecular interactions, while the electron localization function (ELF) revealed atomic shell structures and localized lone pairs, especially around electronegative centers. Molecular docking studies highlighted significant binding interactions of both drugs with the OSR1 kinase protein, with HFTZ exhibiting superior inhibitory potential. Molecular dynamics simulations further confirmed the structural stability and interaction profiles of both drugs within the active site. HCTZ demonstrated a consistent interaction with GLY520, while HFTZ exhibited adaptive binding to the flexible loop regions, especially interacting with LEU473 through its sulfonamide group. These findings provide deep insights into the structural, electronic, and binding characteristics of these antihypertensive agents, supporting their pharmacological relevance and guiding future drug design strategies. This comparative framework highlights how subtle structural variations, such as fluorine substitution in HFTZ, influence electronic delocalization and binding behaviour.

Graphical abstract