Prediction of Protein-Drug Interactions, Pharmacophore Modeling, and Toxicokinetics of Novel Leads for Type 2 Diabetes Treatment
Authors: Mehra Anuradha , Mittal Amit , Vishwakarma Prakhar Kumar 
Published: August 2024

Background:

Small heterocyclic compounds have been crucial in pioneering advances in type 2
diabetes treatment. There has been a dramatic increase in the pharmacological development of novel heterocyclic
derivatives aimed at stimulating the activation of Glucokinase (GK). A pharmaceutical intervention for
diabetes is increasingly targeting GK as a legitimate target. Diabetes type 2 compromises Glucokinase's function,
an enzyme vital for maintaining the balance of blood glucose levels. Medicinal substances strategically
positioned to improve type 2 diabetes management are used to stimulate the GK enzyme using heterocyclic
derivatives.

Objective:

The research endeavor aimed to craft novel compounds, drawing inspiration from the inherent
coumarin nucleus found in nature. The goal was to evoke the activity of the glucokinase enzyme, offering a
tailored approach to mitigate the undesired side effects typically associated with conventional therapies employed
in the treatment of type 2 diabetes.

Methods:

Coumarin, sourced from nature's embrace, unfolds as a potent and naturally derived ally in the quest
for innovative antidiabetic interventions. Coumarin was extracted from a variety of botanical origins, including
Artemisia keiskeana, Mallotus resinosus, Jatropha integerrima, Ferula tingitana, Zanthoxylum schinifolium,
Phebalium clavatum, and Mammea siamensis. This inclusive evaluation was conducted on Muybridge's
digital database containing 53,000 hit compounds. The presence of the coumarin nucleus was found
in 100 compounds, that were selected from this extensive repository. Utilizing Auto Dock Vina 1.5.6 and
ChemBioDraw Ultra, structures generated through this process underwent docking analysis. Furthermore,
these compounds were accurately predicted online log P using the Swiss ADME algorithm. A predictive analysis
was conducted using PKCSM software on the primary compounds to assess potential toxicity.

Results:

Using Auto Dock Vina 1.5.6, 100 coumarin derivatives were assessed for docking. Glucokinase (GK)
binding was significantly enhanced by most of these compounds. Based on superior binding characteristics
compared with Dorzagliatin (standard GKA) and MRK (co-crystallized ligand), the top eight molecules were
identified. After further evaluation through ADMET analysis of these eight promising candidates, it was confirmed
that they met the Lipinski rule of five and their pharmacokinetic profile was enhanced. The highest
binding affinity was demonstrated by APV16 at -10.6 kcal/mol. A comparison between the APV16, Dorzagliatin
and MRK in terms of toxicity predictions using PKCSM indicated that the former exhibited less skin
sensitization, AMES toxicity, and hepatotoxicity.

Conclusion:

Glucokinase is most potently activated by 100 of the compound leads in the database of 53,000
compounds that contain the coumarin nucleus. APV12, with its high binding affinity, favorable ADMET (adjusted
drug metabolic equivalents), minimal toxicity, and favorable pharmacokinetic profile warrants consideration
for progress to in vitro testing. Nevertheless, to uncover potential therapeutic implications, particularly
in the context of type 2 diabetes, thorough investigations and in-vivo evaluations are necessary for benchmarking
before therapeutic use, especially experiments involving the STZ diabetic rat model.