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. 2019 Nov 25;20(23):5913.
doi: 10.3390/ijms20235913.

Model Optimization and In Silico Analysis of Potential Dipeptidyl Peptidase IV Antagonists from GC-MS Identified Compounds in Nauclea latifolia Leaf Extracts

Franklyn Nonso Iheagwam  1   2 , Olubanke Olujoke Ogunlana  1   2 , Shalom Nwodo Chinedu  1   2
Affiliations

Model Optimization and In Silico Analysis of Potential Dipeptidyl Peptidase IV Antagonists from GC-MS Identified Compounds in Nauclea latifolia Leaf Extracts

Franklyn Nonso Iheagwam et al. Int J Mol Sci. .

Abstract

Dipeptidyl peptidase IV (DPP-IV) is a pharmacotherapeutic target in type 2 diabetes. Inhibitors of this enzyme constitute a new class of drugs used in the treatment and management of type 2 diabetes. In this study, phytocompounds in Nauclea latifolia (NL) leaf extracts, identified using gas chromatography-mass spectroscopy (GC-MS), were tested for potential antagonists of DPP-IV via in silico techniques. Phytocompounds present in N. latifolia aqueous (NLA) and ethanol (NLE) leaf extracts were identified using GC-MS. DPP-IV model optimization and molecular docking of the identified compounds/standard inhibitors in the binding pocket was simulated. Drug-likeness, pharmacokinetic and pharmacodynamic properties of promising docked leads were also predicted. Results showed the presence of 50 phytocompounds in NL extracts of which only 2-O-p-methylphenyl-1-thio-β-d-glucoside, 3-tosylsedoheptulose, 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol and vitamin E exhibited comparable or better binding iGEMDOCK and AutoDock Vina scores than the clinically prescribed standards. These four compounds exhibited promising drug-likeness as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties suggesting their candidature as novel leads for developing DPP-IV inhibitors.

Keywords: ADMET; Nauclea latifolia; dipeptidyl peptidase IV; gas chromatography-mass spectroscopy; homology modeling; in silico; molecular docking.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Gas chromatogram of NLE.
Figure 2
Figure 2
Gas chromatogram of NLA.
Figure 3
Figure 3
The (a) global quality estimate makeup, (b) local quality estimate and (c) comparison plots of modeled DPP-IV.
Figure 4
Figure 4
Cartoon representations of (a) 3D modeled Homo sapiens dipeptidyl peptidase IV structure showing α helices (red), β sheet (blue) and loops (green). (b) 3D structural superimposition of 1wcy (blue), modeled DPP-IV (grey) and energy minimized DPP-IV (green).
Figure 5
Figure 5
Representation of the DPP-IV atomic composition.
Figure 6
Figure 6
Representation of the DPP-IV amino acid residues composition.
Figure 7
Figure 7
Quality factor plot of the minimized modeled DPP-IV.
Figure 8
Figure 8
3D verification plot of the minimized modeled DPP-IV structure.
Figure 9
Figure 9
Identified DPP-IV binding pocket as simulated by (a) DoGSiteScorer in gold and (b) PockDrug in blue.
Figure 10
Figure 10
3D and 2D binding poses of (a) 2-O-p-methylphenyl-1-thio-β-d-glucoside, (b) 3-tosylsedoheptulose, (c) 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol, (d) vitamin E, (e) alogliptin and (f) saxagliptin simulated by iGEMDOCK. For each ligand, hydrogen, carbon-hydrogen, unfavorable and π–π bonds are depicted as green, light blue, red and any other colored (purple, magenta, orange and yellow) broken lines respectively.
Figure 10
Figure 10
3D and 2D binding poses of (a) 2-O-p-methylphenyl-1-thio-β-d-glucoside, (b) 3-tosylsedoheptulose, (c) 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol, (d) vitamin E, (e) alogliptin and (f) saxagliptin simulated by iGEMDOCK. For each ligand, hydrogen, carbon-hydrogen, unfavorable and π–π bonds are depicted as green, light blue, red and any other colored (purple, magenta, orange and yellow) broken lines respectively.
Figure 10
Figure 10
3D and 2D binding poses of (a) 2-O-p-methylphenyl-1-thio-β-d-glucoside, (b) 3-tosylsedoheptulose, (c) 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol, (d) vitamin E, (e) alogliptin and (f) saxagliptin simulated by iGEMDOCK. For each ligand, hydrogen, carbon-hydrogen, unfavorable and π–π bonds are depicted as green, light blue, red and any other colored (purple, magenta, orange and yellow) broken lines respectively.
Figure 11
Figure 11
3D and 2D binding poses of (a) 2-O-p-methylphenyl-1-thio-β-d-glucoside, (b) 3-tosylsedoheptulose, (c) 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol, (d) vitamin E, (e) alogliptin and (f) saxagliptin simulated by AutoDock Vina. For each ligand, hydrogen, carbon-hydrogen, unfavorable and π–π bonds are depicted as green, light blue, red and other colored (purple and magenta) broken lines respectively.
Figure 11
Figure 11
3D and 2D binding poses of (a) 2-O-p-methylphenyl-1-thio-β-d-glucoside, (b) 3-tosylsedoheptulose, (c) 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol, (d) vitamin E, (e) alogliptin and (f) saxagliptin simulated by AutoDock Vina. For each ligand, hydrogen, carbon-hydrogen, unfavorable and π–π bonds are depicted as green, light blue, red and other colored (purple and magenta) broken lines respectively.
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