Structural Dynamics of DPP-4 and Its Influence on the Projection of Bioactive Ligands

Dipeptidyl peptidase-4 (DPP-4) is a target to treat type II diabetes mellitus. Therefore, it is important to understand the structural aspects of this enzyme and its interaction with drug candidates. This study involved molecular dynamics simulations, normal mode analysis, binding site detection and analysis of molecular interactions to understand the protein dynamics. We identified some DPP-4 functional motions contributing to the exposure of the binding sites and twist movements revealing how the two enzyme chains are interconnected in their bioactive form, which are defined as chains A (residues 40–767) and B (residues 40–767). By understanding the enzyme structure, its motions and the regions of its binding sites, it will be possible to contribute to the design of new DPP-4 inhibitors as drug candidates to treat diabetes

Methyl divanillate: redox properties and binding affinity with albumin of an antioxidant and potential NADPH oxidase inhibitor

Vanillic acid is a widely used food additive (flavouring agent, JECFA number: 959) with many reported beneficial biological effects. The same is true for its ester derivative (methyl vanillate, JECFA number: 159). Based on the increasing evidence that diapocynin, the dimer of apocynin (NADPH oxidase inhibitor), has some improved pharmacological properties compared to its monomer, here the dimer of methyl vanillate (MV), i.e., methyl divanillate (dimer of methyl vanillate, DMV) was synthesized and studied in the context of its redox properties and binding affinity with human serum albumin (HSA). We found that the antioxidant potency of DMV was significantly increased compared to MV. In this regard, the reduction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical by DMV was 30-fold more effective compared to MV. Ferric ion reduction was 4-fold higher and peroxyl radical reduction was 2.7-fold higher. The interaction with HSA was significantly improved (Stern–Vomer constants, 3.8 × 105 mol−1 L and 2.3 × 104 mol−1 L, for DMV and MV, respectively). The complexation between DMV and HSA was also evidenced by induced circular dichroism (ICD) signal generation in the former due to its fixation in the asymmetric protein pocket. Density-functional calculations (TD-DFT) showed that the ICD spectrum was related to a DMV conformation bearing a dihedral angle of approximately −60°. Similar dihedral angles were obtained in the lowest and most populated DMV cluster poses obtained by molecular docking simulations. The computational studies and experimental displacement studies revealed that DMV binds preferentially at site I. In conclusion, besides being a powerful antioxidant, DMV is also a strong ligand of HSA. This is the first study on the chemical and biophysical properties of DMV, a compound with potential beneficial biological effects9351998319992CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP302793/2016-0; 305541/2017-02014/50926-0; 2016/20549-5; 2016/22014-1The authors gratefully acknowledge financial support from the National Council for Scientific and Technological Development (CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico, grant # 302793/2016-0 and 305541/2017-0), National Institute of Science and Technology – INCT BioNat, grant # 465637/2014-0, and the State of Sao Paulo Research Foundation (FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo, grants # 2014/50926-0, # 2016/20549-5 and # 2016/22014-1