Page 43 - GPD-2-3

Gene & Protein in Disease Effect of phytochemicals in diabetes

structures was downloaded and a total of 85 ligands were interactions of two conventional H-bonds of length 2.45 Å
examined for ADMET testout and drug-likeness features. and 2.20 Å with Leu200; six attractive charge interactions
The qualified ligands and control compound details with Glu205 and Glu194 at lengths of 5.57 Å, 4.27 Å,
are shown in Table 6 and they were then used for lead 3.95 Å, 3.06 Å, 4.79 Å, and 2.96 Å; a salt bridge of 1.84 Å
preparation and docking study. with Glu205 residue; Phe180 of target forms two π-cation
interactions of 4.16 Å and 4.91 Å; and an unfavorable donor-
3.3. ADMET and drug-likeness calculation of ligands
donor interaction of 2.55 Å with Ala202 (Table S1).
Some online tools were used for the drug-likeness Figure 1B presents the binding of vindolinine (CID:
predictions. Out of 85 ligands, only five ligands, 24148538) through the selected pocket site (residue
vindoline (CID: 425978), vindolinine (CID: 24148538),
(+)-vindorosine (CID: 261578), Cr-1 (CID: 5315746), Arg199) of AMPK1 chain A through non-covalent
and Cr-2 (CID: 59908094) were qualified in the toxicity interactions and had a binding affinity of −7.4 kcal/mol
test (mutagenic, carcinogenic, irritation, and reproductive (Table 8). In between the target and the lead, there are
properties). The high, medium, and no-risk zones were three conventional H-bond interactions with Arg182
shown in red, yellow, and green colors, respectively. The and Leu462 of 2.66 Å, 3.08 Å, and 2.20 Å; two π-alkyl
no-risk zone shows that the qualified biomolecules have interactions with Leu462 and Tyr463 of 5.39 Å and 5.14
low or non-toxic effects. The OSIRIS Property Explorer Å, respectively; one π-π stacked interaction with Tyr441 of
estimated values and DruLiTo software customized values 4.13 Å; and an unfavorable positive-positive interaction of
details are presented in Table 7. The data indicated that the 3.97 Å with Arg182 (Table S1).
biomolecules have drug-like properties. Figure 1C shows the attachment of the lead vindoline
3.4. Molecular docking investigation (CID: 425978) with the active site of AMPK1 with non-
covalent interactions and having a binding affinity
3.4.1. AMPK1 targets interaction with lead and control of −6.3 kcal/mol. Their docking pose displays the presence
Intermolecular interaction between metformin (control) of strong intermolecular interactions where Leu462 and
and AMPK1 target has been confirmed by their docked Arg182 residues of the target form two conventional
poses (Figure 1) and had a binding affinity of -4 kcal/mol H-bond interactions of 2.31 Å and 2.30 Å, respectively;
(see Table 8). Figure 1A shows the interaction between chain Gly198 and Gln461 residues form three carbon H-bond
A of AMPK1, pocket residue ARG199, and the control drug interactions of 3.62 Å, 3.59 Å, and 3.56 Å; Leu200 residue
metformin. The complex is formed between them with forms an alkyl interaction of 5.20 Å; and Tyr463 of AMPK1

Table 5. QMEAN scores for the model protein generated using the SWISS‑MODEL server
Receptor Template Model quality estimation (QMEAN scores) Sequence identity Coverage Method Resolution
AMPK 1 4rer. 1.A 0.68±0.05 99.07 0.97 X-ray 4.05Å
AMPK 2 7myj. 2.A 0.73±0.05 99.82 1.00 X-ray 2.95Å
Note: QMEAN scores referred to the degree of nativeness of protein, a score of>0.6 indicated good quality model protein.

Table 6. Ligands selected for lead preparation

Ligand PubChem CID IUPAC name Molecular weight
(g/mol)
Vindolinine CID: 24148538 Methyl (1R,9R,10R,12R,19S,20R)-20-methyl-8,16-diazahexacyclo 336.4
[10.6.1.19,12.01,9.02,7.016,19] icosa-2,4,6,13-tetraene-10-carboxylate
Vindoline CID: 425978 Methyl 11-acetyloxy-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16 diazapentacyclo 456.5
[10.6.1.01,9.02,7.016,19] nonadeca-2 (7),3,5,13-tetraene-10-carboxylate
(+)-Vindorosine CID: 261578 1H-Indolizino (8,1-cd) carbazole-5-carboxylic acid, 3a-ethyl-3a, 4,5,5a, 426.5
6,11,12,13a-octahydro-4,5-dihydroxy-6-methyl-, methyl ester, 4-acetate
CR-1 CID: 5315746 Methyl 12-ethyl-10,11-dihydroxy-8-methyl-8,16-diazapentacyclo 384.5
[10.6.1.01,9.02,7.016,19] nonadeca-2,4,6,13-tetraene-10-carboxylate
CR-2 CID: 59908094 (4-Tert-butyl-12-ethyl-10-formyl-10-hydroxy-5-methoxy-8-methyl-8, 482.6
16-diazapentacyclo [10.6.1.01,9.02,7.016,19] nonadeca-2,4,6,13-tetraen-11-yl) acetate
Metformin CID: 4091 3-(diaminomethylidene)-1,1-dimethylguanidine 129.16

Volume 2 Issue 3 (2023) 5 https://doi.org/10.36922/gpd.0927