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Navigating the chemical space of dipeptidyl peptidase-4 inhibitors.

Shoombuatong W, Prachayasittikul V, Anuwongcharoen N, Songtawee N, Monnor T, Prachayasittikul S, Prachayasittikul V, Nantasenamat C - Drug Des Devel Ther (2015)

Bottom Line: The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 μM and greater than 10 μM, respectively.Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties.Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues.

View Article: PubMed Central - PubMed

Affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.

ABSTRACT
This study represents the first large-scale study on the chemical space of inhibitors of dipeptidyl peptidase-4 (DPP4), which is a potential therapeutic protein target for the treatment of diabetes mellitus. Herein, a large set of 2,937 compounds evaluated for their ability to inhibit DPP4 was compiled from the literature. Molecular descriptors were generated from the geometrically optimized low-energy conformers of these compounds at the semiempirical AM1 level. The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 μM and greater than 10 μM, respectively. Decision tree analysis revealed the importance of molecular weight, total energy of a molecule, topological polar surface area, lowest unoccupied molecular orbital, and number of hydrogen-bond donors, which correspond to molecular size, energy, surface polarity, electron acceptors, and hydrogen bond donors, respectively. The prediction model was subjected to rigorous independent testing via three external sets. Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties. Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues. The results of this study are anticipated to be useful in guiding the rational design of novel and robust DPP4 inhibitors for the treatment of diabetes.

No MeSH data available.


Related in: MedlinePlus

Three different binding modes of interaction of DPP4 inhibitors in the active site of the enzyme.Notes: The identified anchors HB1, HB2, and vdW from the SiMMap server are labeled and shown in cyan and yellow spheres, respectively. Docking poses of two selected inhibitors are visualized herein: the compound with the best SiMMap score (A) and the compound with the lowest half maximal inhibitory concentration values (B). Residues at the active site are shown in green sticks while key interacting residues are labeled and shown in dark grey lines.
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f6-dddt-9-4515: Three different binding modes of interaction of DPP4 inhibitors in the active site of the enzyme.Notes: The identified anchors HB1, HB2, and vdW from the SiMMap server are labeled and shown in cyan and yellow spheres, respectively. Docking poses of two selected inhibitors are visualized herein: the compound with the best SiMMap score (A) and the compound with the lowest half maximal inhibitory concentration values (B). Residues at the active site are shown in green sticks while key interacting residues are labeled and shown in dark grey lines.

Mentions: Molecular docking and subsequent post-docking analyses using the SiMMap server identified the common binding mode of DPP4 inhibitors as well as key interactions with the enzyme. The SiMMap server provided a site-moiety map of the binding pocket along with details on conserved interacting residues, moiety preferences, and interaction types.37 Analyses based on 100 active DPP4 inhibitors revealed three different binding anchors (HB1, HB2, and vdW) and their moiety preferences (Figure 6). The anchor HB1 comprised side chains of Arg125, Glu205, Glu206, and Tyr662 while anchor HB2 contained only the hydroxyl side chain of Tyr547. Both anchors were found to make hydrogen bonds with several nitrogen functional groups (ie, amine-, amide-, imine-, and nitrile-based) as well as ketone-based moieties of the inhibitors. In contrast, the anchor vdW consisted primarily of hydrophobic side chains of Tyr547, Tyr631, Trp659, Tyr662, and Tyr666 as well as the hydroxyl group of the catalytic residue Ser630. This pocket formed van der Waals contacts with aromatic, heterocyclic, and aliphatic moieties of DPP4 inhibitors. It should be noted that from our SiMMap analyses, the anchor HB1 has been known as the S2 pocket, which is involved in key salt bridge interactions of either the free amino terminus of a peptide substrate or the cationic groups of an inhibitor with the carboxylate side chains of Glu205 (and/or Glu206) as well as the guanidinium side chain of Arg125, which also helps stabilize either the amide carbonyl group of a substrate or the ketone moiety of an inhibitor.7,12 The anchor vdW corresponds to the S1 selectivity pocket of the enzyme that has been shown to be occupied with specific benzene- and pyrrolidine-based moieties of the DPP4 inhibitors.7,12


Navigating the chemical space of dipeptidyl peptidase-4 inhibitors.

Shoombuatong W, Prachayasittikul V, Anuwongcharoen N, Songtawee N, Monnor T, Prachayasittikul S, Prachayasittikul V, Nantasenamat C - Drug Des Devel Ther (2015)

Three different binding modes of interaction of DPP4 inhibitors in the active site of the enzyme.Notes: The identified anchors HB1, HB2, and vdW from the SiMMap server are labeled and shown in cyan and yellow spheres, respectively. Docking poses of two selected inhibitors are visualized herein: the compound with the best SiMMap score (A) and the compound with the lowest half maximal inhibitory concentration values (B). Residues at the active site are shown in green sticks while key interacting residues are labeled and shown in dark grey lines.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539085&req=5

f6-dddt-9-4515: Three different binding modes of interaction of DPP4 inhibitors in the active site of the enzyme.Notes: The identified anchors HB1, HB2, and vdW from the SiMMap server are labeled and shown in cyan and yellow spheres, respectively. Docking poses of two selected inhibitors are visualized herein: the compound with the best SiMMap score (A) and the compound with the lowest half maximal inhibitory concentration values (B). Residues at the active site are shown in green sticks while key interacting residues are labeled and shown in dark grey lines.
Mentions: Molecular docking and subsequent post-docking analyses using the SiMMap server identified the common binding mode of DPP4 inhibitors as well as key interactions with the enzyme. The SiMMap server provided a site-moiety map of the binding pocket along with details on conserved interacting residues, moiety preferences, and interaction types.37 Analyses based on 100 active DPP4 inhibitors revealed three different binding anchors (HB1, HB2, and vdW) and their moiety preferences (Figure 6). The anchor HB1 comprised side chains of Arg125, Glu205, Glu206, and Tyr662 while anchor HB2 contained only the hydroxyl side chain of Tyr547. Both anchors were found to make hydrogen bonds with several nitrogen functional groups (ie, amine-, amide-, imine-, and nitrile-based) as well as ketone-based moieties of the inhibitors. In contrast, the anchor vdW consisted primarily of hydrophobic side chains of Tyr547, Tyr631, Trp659, Tyr662, and Tyr666 as well as the hydroxyl group of the catalytic residue Ser630. This pocket formed van der Waals contacts with aromatic, heterocyclic, and aliphatic moieties of DPP4 inhibitors. It should be noted that from our SiMMap analyses, the anchor HB1 has been known as the S2 pocket, which is involved in key salt bridge interactions of either the free amino terminus of a peptide substrate or the cationic groups of an inhibitor with the carboxylate side chains of Glu205 (and/or Glu206) as well as the guanidinium side chain of Arg125, which also helps stabilize either the amide carbonyl group of a substrate or the ketone moiety of an inhibitor.7,12 The anchor vdW corresponds to the S1 selectivity pocket of the enzyme that has been shown to be occupied with specific benzene- and pyrrolidine-based moieties of the DPP4 inhibitors.7,12

Bottom Line: The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 μM and greater than 10 μM, respectively.Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties.Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues.

View Article: PubMed Central - PubMed

Affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.

ABSTRACT
This study represents the first large-scale study on the chemical space of inhibitors of dipeptidyl peptidase-4 (DPP4), which is a potential therapeutic protein target for the treatment of diabetes mellitus. Herein, a large set of 2,937 compounds evaluated for their ability to inhibit DPP4 was compiled from the literature. Molecular descriptors were generated from the geometrically optimized low-energy conformers of these compounds at the semiempirical AM1 level. The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 μM and greater than 10 μM, respectively. Decision tree analysis revealed the importance of molecular weight, total energy of a molecule, topological polar surface area, lowest unoccupied molecular orbital, and number of hydrogen-bond donors, which correspond to molecular size, energy, surface polarity, electron acceptors, and hydrogen bond donors, respectively. The prediction model was subjected to rigorous independent testing via three external sets. Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties. Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues. The results of this study are anticipated to be useful in guiding the rational design of novel and robust DPP4 inhibitors for the treatment of diabetes.

No MeSH data available.


Related in: MedlinePlus