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DPP-IV and FAP-α as Targets of Drug Design: A Comparative Structural Analysis of Molecular Features and Biological
Michelle Cristiane Melo Reis Martins1, Simone Queiroz Pantaleão2, Eric Allison Philot3
1Center for Natural and Human Sciences, Federal University of ABC, Santo André, SP, Brazil.
Introduction/Objective:
This study aims to compare the structural and functional features of DPP-IV and FAP-α to identify ligand characteristics relevant to selective inhibition.
Methods:
To this end, we performed enzyme superposition, binding-site characterization, molecular docking, normal mode analysis, molecular dynamics simulations, and binding-site detection.
Results And Discussion:
The analyses revealed distinct residue compositions in the binding pockets, indicating a more polar environment in DPP-IV and a more hydrophobic environment in FAP-α. Key interactions between DPP-IV and bioactive compounds included hydrogen bonds and π-π contacts involving Ser630, Tyr622, and Tyr666, which were associated with ligand regions, such as the trifluorophenyl and cyclohexylamine groups. Normal mode calculations revealed differences in functional motions among the biological targets under study, and molecular dynamics simulations confirmed ligand stability and the structural impact on binding sites.
Conclusion:
These findings highlight structural elements that can guide the design of more selective drug candidates for type 2 diabetes therapy.
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