Research Article Articalticle Bioinformatics: Co Authors
Research Article Articalticle Bioinformatics: Co Authors
Research Article Articalticle Bioinformatics: Co Authors
Corresponding Author
PAPPU SRINIVASAN
1
Department of Bioinformatics, Alagappa University, Karaikudi –
630 003, India
Co Authors
1
ARUMUGAM SUDHA, 2RAMAR MANIKANDAN AND
3
CHINNASAMY ARULVASU
2
Department of Animal Health & Management, Alagappa University, Karaikudi – 630 003, India
3
Department of Zoology, University of Madras, Chennai – 600 025
ABSTRACT
Type 2 diabetes is one of the major life threatening diseases worldwide these cases are
progressing at an incremental rate every year and number of research works are going on to
control the disease by targeting its enzymes or proteins. The medicinal properties of Vitex negundo
and one of its compounds, 1, 2 disubstituted idopyranose (C23H28O12) was checked against
diabetes mellitus by molecular docking with various proteins which are involved in the carbohydrate
metabolism. The inhibitor, 1, 2 disubstituted idopyranose was found to be increased insulin
sensitivity and normalize blood glucose level by binding in the active sites of the protein and thus
useful therapeutic agent for the herbal therapy of diabetes. The docking method to explore the
ability of 1, 2 disubstituted idopyranose bound to the active binding site in the proteins and showed
that the inhibitor is the best binder of the present study. We concluded that the natural products with
interesting biological properties and structural diversity have often served as valuable lead drug
candidates for the treatment of human diseases and also it replaces the chemically synthesized
drugs which cause side effects.
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a genetically two forms, i.e., as a soluble homo-dimer and
heterogeneous, polygenic disease with a as a type II integral plasma membrane
complex inheritance pattern and is caused by glycoprotein which is abundantly expressed on
genetic predisposition and environmental factors a variety of cell surfaces (Bjelke et al., 2004;
(LeRoith, 2002). The disease is characterized by Abbott and Gorrell, 2002; Lambeir et al., 1997;
altered expression of many genes and their Duke-Cohan et al., 1996). DPP-IV deactivates
products in several tissue types (Gerich, 1998; the incretin hormones GLP-1 and GIP by
Gloyn, 2003). Number of proteins was cleaving the penultimate proline or alanine
considered as a target to control the diabetes from the N-terminal (P1-position) of the
mellitus. In the present study, four proteins such peptide, since the intact N-terminal ends of
as human maltase-glucoamylase (MGA), both GLP-1 and GIP are essential for biological
dipeptidyl peptidase-4 (DPP-4), aldose activity (Adelhorst et al., 1994; Rolin et al.,
reductase (AR) and glycogen synthase kinase-3 2004). The cleavage of the N-terminal
(GSK-3) are considered as targets for the dipeptide segment by DPP-IV plays an
inhibitor, 1, 2 disubstituted idopyranose (C23- important role in maintaining glucose
H28O12), derived from the leaves of the medicinal homeostasis. Thus, shielding incretin
plant, Vitex negundo Linn (Verbanaceae). MGA hormones from catastrophic effects of DPP-IV
is an enzyme responsible for catalyzing the last enzyme by the administration of inhibitors will
glucose releasing step in starch digestion. MGA maintain the concentrations of incretin
accounts for all glucoamylase activity, 20% of hormones and prolong their proficient
the maltase activity and 1% of the sucrase antidiabetic action. Aldose reductase (AR) is
activity (Semenza et al., 1989). Human MGA the first enzyme of the polyol pathway and is
encoded by the gene MGAM (Buford et al., widely distributed in mammalian tissues. Due
2003; Roy et al., 2002) is an alpha glucosidase to increased aldose reductase activity, the
responsible for hydrolysis of α-1, 4- linkages accumulation of intracellular sorbitol is also
from the non-reducing end of the maltose raised. It implicates the development of various
oligosaccharides (Nichols et al., 1998) and secondary complications of diabetes mellitus
belongs to glycoside hydrolase family 31. It is (Muthenna et al., 2009). Glycogen synthase
type II membrane protein, 1857 amino acids in kinase-3 (GSK-3) is a unique multifunctional
length anchored in the brush border epithelial serine/threonine kinase and it was inactivated
cells of the small intestine. Dipeptidyl peptidase- by phosphorylation. In response to insulin
IV (DPP-IV) is a multifunctional protein involved binding, PKB/AKT phosphorylates GSK-3 on
in many physiological processes such as binding serine 9, which prevents the enzyme from
protein, receptor and proteolytic enzyme. DPP- phosphorylating glycogen synthase (Frame et
IV was discovered in the late 80’s, as a serine al., 2001; Mukai et al., 2002; Doble and
peptidase belonging to the S9b protein family Woodgett, 2003). Unphosphorylated glycogen
(Ogata et al., 1989). This ecto-enzyme exists in synthase is active and able to synthesize
Figure 1
1, 2 disubstituted idopyranose
Figure 2 Figure 3
Maltase Glucoamylase (2qmj) Dipeptidyl peptidase-4 (3f8s)
By docking the known ligand acarbose with four target proteins, maltase glucoamylase
maltase glucoamylase (Sim et al., 2008), PF2 (PDB ID: 2qmj), dipeptidyl peptidase-4 (PDB
with dipeptidyl peptidase-4 (Ammirati et al., ID: 3f8s), aldose reductase (PDB ID: 3g5e) and
2009), IDD740 with aldose reductase (Van et al., glycogen synthase kinase-3 (PDB ID: 3f7z)
2009) and oxadiozole with GSK-3 (Saitoh, M., separately. In that 32 poses, the best 10 poses
2009), RMSD were checked for the reliability of (1 to 10) were selected according to the Glide
docking method in reproducing the XP score and lowest energy docked
experimentally observed binding mode of the conformation and subjected to the energy
proteins. The ligand, 1, 2 disubstituted minimization using Liasion module. Table 1
idopyranose (C23H28O12) prepared with 32 poses summarizes the result of the docking study
using LigPrep (Fig. 2 6, 7) were docked with presented as Glide score and Glide energies.
Figure 6
1, 2 disubstituted idopyranose- 32 poses
* Ligand pose showing high glide score and low bound energy
Figure 8 Figure 9
1, 2 disubstituted idopyranose 1, 2 disubstituted idopyranose
bound with 2qmj bound with 3f8s
Figure 10 Figure 11
1, 2 disubstituted idopyranose 1, 2 disubstituted idopyranose
bound with 3f7z bound with 3g5e
Table 4
ADME/T properties of 1, 2 disubstituted idopyranose
Descriptors/Properties Value
Mol_MW 498.483
QPlogMDCK 1.921
QPlogHERG -3.135
LROF 2
QPPCaco 4.709
Stars 2
QPlogKp -5.288
QPlogS -2.779
QPlogBB -2.889
QPpolrz 42.933