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In silico Studies on the Interaction Between Bioactive Ligands and DPPIV: Insights on Potential Candidates for the Treatment of type 2 Diabetes Mellitus

Author(s):

Michelle Cristiane Melo Reis Martins, Simone Queiroz Pantaleao, Michell de Oliveira Almeida, Karen Cacilda Weber and Kathia Maria Honorio*   Pages 1 - 17 ( 17 )

Abstract:


Introduction: The enzyme called dipeptidyl peptidase IV (DPP-IV) is related to the glycemic control associated with the stimulation of the pancreas to produce insulin. So, its inhibition is a good strategy for the treatment of type 2 diabetes mellitus.

Methods: In this study, we have employed molecular modeling strategies such as CoMFA, molecular docking, molecular dynamics, and binding free energy calculations of a set of DPP-IV inhibitors in order to understand the main characteristics related to the biological activity of these ligands against the enzyme.

Results: The models obtained from CoMFA presented significant values of internal (0.768) and external (0.988) validations. Important interactions with some residues, such as Glu205, Tyr666, Arg125, Ser630, Phe357 and Tyr662, were also identified. In addition, calculations of the electronic properties allowed relating the LUMO and HOMO energies with the biological activity of the compounds studied. The results obtained from the molecular dynamics simulations and the SIE calculations (ΔG) indicated that the inhibitor 40 increases the stability of the DPP-IV target.

Conclusions: Therefore, from this study it is possible to propose molecular modifications of these DPP-IV inhibitors in order to improve their potential to treat type 2 diabetes.

Keywords:

Diabetes, DPP-IV, Inhibitors, Docking, CoMFA, Molecular Dynamics, Binding Free Energy

Affiliation:

Center for Natural and Human Sciences, Federal University of ABC, 09210-170, Santo André, SP, Center for Natural and Human Sciences, Federal University of ABC, 09210-170, Santo André, SP, São Carlos Institute of Chemistry, University of São Paulo, 13566-590, São Paulo, SP, Department of Chemistry, Federal University of Paraiba, 58051970, João Pessoa, Center for Natural and Human Sciences, Federal University of ABC, 09210-170, Santo André, SP



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