Title:Molecular Docking, Pharmacophore Mapping, and Virtual Screening of Novel Glucokinase Activators as Antidiabetic Agents
Volume: 21
Issue: 4
Author(s): Anuradha Mehra, Amit Mittal*Divya Thakur
Affiliation:
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-
Delhi G.T. Road (NH-1), Phagwara (Punjab), 144411, India
Keywords:
Glucokinase activators, diabetes, docking, oxadiazole derivatives, binding affinity, drug design, virtual screening, pharmacophore, molecular docking, AutoDock Vina.
Abstract:
Background: A pivotal impetus has led to the development of numerous small molecules
to develop therapeutic strategies for type 2 diabetes. Novel heterocyclic derivatives are now available
with expansive pharmacological activity designed specifically to activate Glucokinase (GK) in
the body. This target is of particular significance in antidiabetic drug design since it is a newly validated
target. Individuals with type 2 diabetes are unable to maintain blood glucose homeostasis due
to impaired glucokinase function. The novel approach to managing type 2 diabetes relies on utilizing
heterocyclic derivatives to activate the GK enzyme, also known as a metabolic enzyme.
Objective: In this research endeavor, the primary objective was to improve drug delivery while minimizing
adverse effects by using molecules that activate glucokinase.
Methods: There are 53,000 compounds included in Maybridge's online repository, which has been
subjected to rigorous scrutiny. Eight two compounds that encompass the specific oxadiazole core
were selectively extracted from this extensive collection. ChemBioDraw Ultra was used for structural
drawing, and AutoDock Vina 1.5.6 was used to perform docking analysis. For the online prediction
of log P, the SwissADME algorithm was employed. A PKCSM software program was used
to predict toxicity for leading compounds.
Results: Among all of the compounds, AD80 and AD27 displayed the highest affinity for GK receptors.
These compounds, by adhering to Lipinski’s Rule of Five, exhibited good absorption and
excretion profiles through the gastrointestinal (GI) tract. Lipinski’s Rule of Five refers to physicochemical
properties that favor good oral bioavailability, and these specifications are zero to five hydrogen
bond donors, zero to ten hydrogen bond acceptors, molecular weight below 500, and log P
no more than five. These criteria ensure that the compounds of the invention have acceptable solubility
and permeability, which are vital prerequisites when given orally, to be absorbed via the gastrointestinal
wall, metabolized, and found in the urine. Therefore, the chance of drug candidates exhibiting
favorable pharmacokinetic characteristics is increased, enhancing their chances of being
developed for oral administration. In comparison with standard drugs Dorzagliatin as a glucokinase
activator (GKA) and MRK (co-crystallized ligand), these compounds exhibit no skin sensitization,
AMES toxicity, or hepatotoxicity.
Conclusion: The recently designed lead molecules exhibit an improved pharmacokinetic profile,
enhanced binding affinity, and minimal toxicity based on the computational study, potentially making
them suitable candidates for further optimization as glucokinase activators.
