Title:Inclusive Drug Designing of Novel Indole Derivatives using Rationale, Pharmacophore Mapping and Molecular Docking
Volume: 24
Issue: 3
Author(s): Anuradha Mehra, Amit Mittal*, Rahul Sharma, Rekha Sangwan and Aryan Mehra
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, indole derivatives, docking, binding affinity, SAR.
Abstract:
Background: The presence of insufficient insulin signaling in type 2 diabetes arises
due to either insulin resistance or impaired insulin secretion, ultimately leading to elevated blood
glucose levels, a condition known as hyperglycemia. Diabetes poses a pervasive worldwide
challenge, with its prevalence steadily surging in both developed and developing nations. A
promising avenue for improving the management of diabetes type 2 involves the exploration of
glucokinase activators as an innovative therapeutic target. Notably, a recent breakthrough in this
area has been the market approval granted by the Japanese FDA for the use of the innovative
GKA, Dorzagliatin, in the treatment of diabetes type 2.
Objectives: To augment the management of diabetes type 2 and mitigate the undesirable side
effects linked to prolonged use of conventional medications, this research endeavor sought to
create innovative glucokinase activators.
Methods: The ZINC database yielded a collection of 56 compounds, each showcasing a 40%
structural similarity to 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid. These compounds,
all featuring the distinctive indole core, were meticulously selected for further investigation.
Structural illustrations were crafted using ChemBioDraw Ultra, and 1.5.6 AutoDock Vina was
for molecular docking. The Swiss ADME algorithm facilitated online log P predictions, while
the software PKCSM was utilized to forecast the toxicity profiles of the leading compounds.
DFT analysis was done to ensure the stability of compounds by using Gaussian 16 quantum
chemistry software and Mulliken charge distributions used to optimize molecular geometries.
Results: Among all the compounds, RS33 and RS37 exhibited the highest affinities for GK
receptors, with the docking scores of -8.93 and -8.44 kcal/mol, respectively. These compounds
follow Lipinski’s Rule, indicating promising absorption and excretion profiles
through the gastrointestinal tract. Compared to standard drugs Dorzagliatin (GKA) and MRK
(co-crystallized ligand), both RS33 and RS37 demonstrate no AMES toxicity, skin sensitization,
and hepatotoxicity. RS43 is the most stable compound as it has high ΔE, η, and χ in DFT
analysis.
Conclusion: The novel-designed lead molecules demonstrate an enhanced pharmacokinetic
profile, superior binding affinity, and minimal toxicity, based on computational study. These
attributes make them promising candidates for further optimization as glucokinase activators.
