Exploring Type II Diabetes Inhibitors from Genus Daphne Plant-species: An Integrated Computational Study
Authors: Nazir Hafiza Ayesha , Shafiq Nusrat , Brogi Simone , Nazli Zill-i-Huma , Khan Jallat , Rashid Maryam , Parveen Shagufta 
Published: April 2024

Background:
Plant species of the genus Daphne clasps a historical background with a
potential source of bioactive phytochemicals such as flavonoids and daphnodorins. These compounds
manifest a significant chemotaxonomic value in drug discovery. Their flair comprehensive
pharmacological, phytochemical, biological, catalytic, and clinical utilities make them exclusively
unique. This study was conducted to investigate the optimization and structure-based virtual
screening of these peculiar analogs. The majority of the active constituents of medicines are obtained
from natural products. Previously, before the invention of virtual screening methods or
techniques, almost 80% of drugs were obtained from natural resources. Comparing reported data
to drug discovery from 1981 to 2007 signifies that half of the FDA-approved drugs are obtained
from natural resources. It has been reported that structures of natural products that have particularities
of structural diversity, biochemical specification, and molecular properties make them suitable
products for drug discovery. These products basically have unique chiral centers which increase
their structural complexity than the synthesized drugs.

background:
Daphnodorins and their analogues are contemplated as pharmacologically significant scaffolds that have demonstrated numerous biological activities such as antifungal and insecticidal activities [17] antibacterial, cytotoxic, antiviral, anti-HIV activity, antioxidant activity [18], inhibitory activity against ∝-glucosidase and angiotensin II formation [19]. Recent pharmacological studies have manifested their efficient and versatile anti-inflammatory, anti-oxidant and protein glycation inhibition activities [20].

Method:
This work aimed to probe the use of daphnodorins analogs for the first time as antidiabetic
inhibitors based on significant features and to determine the potential of daphnodorin analogs
as antidiabetic inhibitors through computational analysis and structure-based virtual screening. A
dataset of 38 compounds was selected from different databases, including PubChem and ZINC,
for computational analysis, and optimized compounds were docked against various co-crystallized
structures of inhibitors, antagonists, and receptors which were downloaded from PDB by using
AutoDock Vina (by employing Broyden-Fletcher-Goldfarb-Shanno method), Discovery studio
visualizer 2020, PYMOL (Schrodinger). Docking results were further validated by Molecular dynamic
simulation and MM-GBSA calculation. Quantitative structure-activity relationship (QSAR)
was reported by using Gaussian 09W by intimating Density Functional Theory (DFT). Using this
combination of multi-approach computational strategy, 14 compounds were selected as potential
exclusive lead compounds, which were analyzed through ADMET studies to pin down their druglike
properties and toxicity.

objective:
Optimized compounds were docked against various co-crystallized structures of antidiabetic drug targets using AutoDock Vina and Discovery studio. Using this approach, 14 compounds were selected as potential exclusive lead compounds, which were analyzed through ADMET studies to pin down their drugs-like properties and toxicity and subjected to measure significant parameters such as dipole moment, electronic energy, frontier molecular orbitals (FMO) energy, and the hardness of molecules by performing DFT.

Result:
At significant phases of drug design approaches regular use of molecular docking has
helped to promote the separation of important representatives from 38 pharmaceutically active
compounds by setting a threshold docking score of -9.0 kcal/mol which was used for their exposition.
Subsequently, by employing a threshold it was recognized that 14 compounds proclaimed
this threshold for antidiabetic activity. Further, molecular dynamic simulation, MM-GBSA, ADMET,
and DFT results screened out daphnegiralin B4 (36) as a potential lead compound for developing
antidiabetic agents.

method:
Molecular docking, DFT, MD Simulation, ADMET

Conclusion:
Our analysis took us to the conclusion that daphnegiralin B4 (36) among all ligands
comes out to be a lead compound having drug-like properties among 38 ligands being non-carcinogenic
and non-cytotoxic which would benefit the medical community by providing significant
drugs against diabetes. Pragmatic laboratory investigations identified a new precursor to open new
doors for new drug discovery.

result:
Hit to lead, out of 38 daphnodorins, 14 compounds were exclusively selected as lead compounds, and from these leads, one compound was chosen as a pre-eminent antidiabetic agent.

conclusion:
Hit to lead, out of 38 daphnodorins, 14 compounds were exclusively selected as lead compounds, and from these leads, one compound was chosen as a pre-eminent antidiabetic agent.