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<p>Inhibition of the biological activity of the α-glucosidase enzyme may prevent diabetes mellitus. In this context, a number of indole-pyridine carbonitrile derivatives were studied using computational methods such as 3D-QSAR, molecular docking, ADMET properties, and molecular dynamics (MD) simulations. The significance of hydrophobic, electrostatic, and H-bond acceptor fields on α-glucosidase inhibitory activity was demonstrated by the 3D-QSAR investigations. High reliability was demonstrated by the developed CoMSIA/EHA model, as evidenced by an essential value of the coefficient of determination (R<sup>2</sup> = 0.958) and an appropriate value of the cross-validation coefficient Q<sup>2</sup> = 0.64. The validity of the model is further supported by a high value of the prediction coefficient for the test set (<InlineEquation ID="IEq1"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="42250_2025_1244_Article_IEq1.gif" Format="GIF" Height="23" Rendition="HTML" Resolution="72" Type="Linedraw" Width="87" /> </InlineMediaObject> <EquationSource Format="TEX">\({\text{R}}_{{{\text{pred}}}}^{2} = 0.94\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <msubsup> <mtext>R</mtext> <mrow> <mtext>pred</mtext> </mrow> <mn>2</mn> </msubsup> <mo>=</mo> <mn>0.94</mn> </mrow> </math></EquationSource> </InlineEquation>). Molecular docking results revealed that compounds with high binding affinity also had high inhibitory efficacy. In addition, ADMET properties were assessed to determine whether these newly developed compounds were likely to be chosen as potential drugs. Finally, to assess the binding stability of the selected ligands to α-glucosidase and verify the molecular docking findings, molecular dynamics simulations were performed with a total duration of 100 ns. The results of this study provide a basis for the development of new molecules with higher inhibitory activities and diverse pharmacological characteristics.</p>

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Indole-Pyridine Carbonitriles as Potential Anti-diabetic Agents: A Computational Study Using 3D-QSAR, Molecular Docking, ADME-Tox and Molecular Dynamics Simulations

  • 期刊论文

  • 发表日期：

    2025年3月7日

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  • Lhoucine Naanaai,
  • Mohamed Ouabane,
  • Abdellah El Aissouq,
  • Abdelkrim Guendouzi,
  • Hicham Zaitan,
  • Mohammed Bouachrine,
  • Fouad Khalil

摘要

Inhibition of the biological activity of the α-glucosidase enzyme may prevent diabetes mellitus. In this context, a number of indole-pyridine carbonitrile derivatives were studied using computational methods such as 3D-QSAR, molecular docking, ADMET properties, and molecular dynamics (MD) simulations. The significance of hydrophobic, electrostatic, and H-bond acceptor fields on α-glucosidase inhibitory activity was demonstrated by the 3D-QSAR investigations. High reliability was demonstrated by the developed CoMSIA/EHA model, as evidenced by an essential value of the coefficient of determination (R2 = 0.958) and an appropriate value of the cross-validation coefficient Q2 = 0.64. The validity of the model is further supported by a high value of the prediction coefficient for the test set ( \({\text{R}}_{{{\text{pred}}}}^{2} = 0.94\) R pred 2 = 0.94 ). Molecular docking results revealed that compounds with high binding affinity also had high inhibitory efficacy. In addition, ADMET properties were assessed to determine whether these newly developed compounds were likely to be chosen as potential drugs. Finally, to assess the binding stability of the selected ligands to α-glucosidase and verify the molecular docking findings, molecular dynamics simulations were performed with a total duration of 100 ns. The results of this study provide a basis for the development of new molecules with higher inhibitory activities and diverse pharmacological characteristics.