Abstract
BackgroundThere has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a) to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c) to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site.Methodology/Principal FindingsWe predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity). Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives.Conclusions/SignificanceWe have demonstrated that our virtual-screening protocol was successful in identifying novel lead compounds for developing more potent DPP-IV inhibitors.
Highlights
Type 2 diabetes mellitus (T2DM) is considered to be the ‘‘epidemic of the 21st century’’ and, the development of new therapies is one of the main challenges in drug discovery today [1]
There are currently 54 entries for dipeptidyl peptidase-IV (DPP-IV) in the Protein Data Bank (PDB; http://www.pdb.org; see Table 1) [20] but only 10 of those entries correspond to validated complexes of the native enzyme with potent reversible inhibitors of a non-peptide nature
In order to define a common background for DPP-IV inhibition, we identified features of inhibitors that make the most important contributions to the bioactivity of the ligand by first superposing all 10 PDB files
Summary
Type 2 diabetes mellitus (T2DM) is considered to be the ‘‘epidemic of the 21st century’’ and, the development of new therapies is one of the main challenges in drug discovery today [1]. The inhibition of human dipeptidyl peptidase-IV (DPP-IV; EC 3.4.14.5) has emerged as a new treatment option for T2DM [3]. This enzyme belongs to the serine protease family and selectively removes N-terminal dipeptides from substrates containing proline or alanine as the second residue. GIP is produced by the duodenal K-cells and is extensively involved in glucose metabolism by enhancing insulin secretion [6]. Both peptides have very short half-lives (4 min for GIP and only 1–2 min for GLP-1) because of their rapid degradation by DPP-IV. The main goals of this study were (a) to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c) to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site
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