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Gene & Protein in Disease Effect of phytochemicals in diabetes

Glu279 of 3.45 Å; single unfavorable positive-positive had passed the test, whereas the others such as vindoline
contact with Lys260 of 3.81 Å. The binding energy between (CID: 425978), (+)-vindorosine (CID: 261578), and Cr-2
them is −5.3 kcal/mol (Table S2). (CID: 59908094) were unable to be detected, means they
Comparison between the potential energy of metformin may cross the BBB [46,47] .
along with the biomolecules of C. roseus on the target, we In the journey of in silico docking analysis, we found that
found that the tested compounds’ potential energy varies metformin and the C. roseus alkaloids bind with chain A of
from −6.2 to −5.3 kcal/mol and has a lower potential AMPK1 pocket residue Arg199 and with chain A of AMPK2
energy than the control (−4.2 kcal/mol) (Table 9). Hence, pocket residue Glu264, other than substrate binding groves
it is predicted that the tested C. roseus alkaloids can bind of AMPK (Thr172). Hence, metformin and the biomolecules
strongly with the target and are more potent activators of act as modulators and indirect AMPK activators, which
AMPK2 than metformin. activate AMPK by enhancing the AMP: ATP ratio by
inhibiting complex I of the respiratory chain of mitochondria
4. Discussion and by intracellular accumulation of calcium [19,53,54] .
Diabetes mellitus initially promotes hyperglycemia but in The docking result of the present study indicates
chronic cases, it moves toward a multi-factorial disease that vindolinine has a strong binding affinity with target
situation. The current investigation supports that C. roseus AMPK1 and AMPK2 with binding energy values of
alkaloids are powerful stimulators of AMPK and have −7.4 kcal/mol and −5.6 kcal/mol, respectively. Similarly,
antihyperglycemic properties . The SOSUI prediction the binding energy of vindoline with target AMPK1 and
[51]
result shows that human AMPK1 (UniProt ID Q13131) is AMPK2 is −6.3 kcal/mol and −6.2 kcal/mol, respectively;
a soluble protein and made up of 559 AA, instead of 548 (+)-vindorosine is −6.3 kcal/mol and −5.6 kcal/mol,
AA as reported in a previous paper , whereas AMPK2 respectively; Cr-1 is −6.4 kcal/mol and −5.3 kcal/mol,
[52]
(UniProt ID P54646) is a membrane-bound protein and respectively; and Cr-2 is −6.1 kcal/mol and −5.3 kcal/mol,
made up of 552 AA (Table 1). respectively (Tables 8 and 9). The binding energy of the
The ADMET test results (Table 7) have shown that metformin is −4.0 kcal/mol with AMPK1 and −4.2 kcal/mol
putative drug candidates of C. roseus phytochemicals obey with AMPK2. Based on the outcome, it is concluded
the Lipinski rule, that is, partition coefficient (cLogP) ≤ that the C. roseus alkaloids vindoline (CID: 425978),
5, which means the compounds have good hydrophilicity vindolinine (CID: 24148538), (+)-vindorosine (CID:
and can engross quickly in the cells. The biomolecules 261578), Cr-1 (CID: 5315746), and Cr-2 (CID: 59908094)
have a high opportunity of absorption in the oral and stimulate AMPK1 and AMPK2 more effectively than
alimentary canal after administration. The standard metformin. Numerous researches and literature found
parameter for the logarithmic assessment of aqueous that the C. roseus plant has a hypoglycemic effect and is
solubility (LogS) is 0 to −4 at 25°C, pH = 7.5, and our superior to biguanides (e.g., metformin). Furthermore, its
result for the majority of ligands candidate is ≤ −4 mol/lit extract decreases the risk of diarrhea-related toxicity (a
[21]
which means that the biomolecules have better absorption side effect of metformin) .
and distribution features. The molecular weight ≤ 500 for As per the thermodynamic principle, “the lesser the
the ligands represents their small sizes leading to a high Gibbs free energy or potential energy, the higher the
opportunity of arriving at the site of action and a high complex stability”. The descending order of binding
possibility of activity on the target site. The standard affinity of AMPK1 with different ligands is vindolinine
criteria for topological polar surface area (TPSA) are ≤140 (−7.4 kcal/mol) > Cr-1 (−6.4 kcal/mol) > vindoline (−6.3
Å whereas the result shows TPSA ≤100 Å, indicating a kcal/mol) = (+)-vindorosine (−6.3 kcal/mol) > Cr-2
molecule has a low polar surface and the ability to infuse (−6.1 kcal/mol) > metformin (−4.0 kcal/mol). Whereas
cells with high surface region for action, thus, they have the descending order of binding affinity of AMPK2 with
a high transport properties or membrane permeability. different ligands is vindoline (-6.2 kcal/mol) > vindolinine
Drug-likeness value varies from 0.58 to 3.95; the positive (-5.6 kcal/mol) = (+)-vindorosine (-5.6 kcal/mol) > Cr-1
and higher value indicates molecules contain the majority (-5.3 kcal/mol) = Cr-2 (-5.3 kcal/mol) > metformin (-4.2
of fragments having biological action or drug-likeness kcal/mol). The general binding affinity of biomolecules
features. The drug-score result varies from 0.49 to 0.84, with AMPK1 appeared to be greater than with AMPK2,
which means that ligands have the potential to meet the which is likely due to the globular and soluble nature of
criteria as a drug. The blood-brain barrier (BBB) crossing AMPK1. Among all ligands, vindolinine (−7.4 kcal/mol)
ability was tested by DruLiTo software, which shows that is the strongest stimulator of AMPK1 whereas vindoline
vindolinine (CID: 24148538) and Cr-1 (CID: 5315746) (−6.2 kcal/mol) is of AMPK2.

Volume 2 Issue 3 (2023) 9 https://doi.org/10.36922/gpd.0927