Inclusive Drug Designing of Novel Indole Derivatives using Rationale, Pharmacophore Mapping and Molecular Docking

Area of Science:

• Medicinal Chemistry
• Computational Drug Design
• Pharmacology

Background:

• Type 2 diabetes is characterized by hyperglycemia due to insulin resistance or impaired insulin secretion.
• Glucokinase activators (GKAs) represent a promising therapeutic target for type 2 diabetes management.
• Recent approval of Dorzagliatin in Japan highlights the clinical potential of GKAs.

Purpose of the Study:

• To design novel glucokinase activators (GKAs) for improved type 2 diabetes management.
• To mitigate side effects associated with conventional diabetes medications.
• To identify lead compounds with enhanced pharmacokinetic and safety profiles.

Main Methods:

• Virtual screening of 56 compounds structurally similar to 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid from the ZINC database.
• Molecular docking using AutoDock Vina to assess binding affinity to GK receptors.
• In silico prediction of pharmacokinetic properties (ADME) using Swiss ADME and toxicity profiles using PKCSM.
• Density Functional Theory (DFT) analysis with Gaussian 16 for compound stability assessment.

Main Results:

• Compounds RS33 and RS37 demonstrated high binding affinities to GK receptors (-8.93 and -8.44 kcal/mol, respectively).
• RS33 and RS37 adhere to Lipinski's Rule, suggesting favorable oral absorption and excretion.
• RS33 and RS37 exhibited no AMES toxicity, skin sensitization, or hepatotoxicity compared to Dorzagliatin and MRK.
• Compound RS43 showed the highest stability based on DFT analysis (high ΔE, η, χ).

Conclusions:

• The computationally designed lead molecules exhibit superior binding affinity and favorable pharmacokinetic profiles.
• These novel GKAs demonstrate minimal toxicity, indicating a promising safety profile.
• The identified compounds are strong candidates for further preclinical development as glucokinase activators for type 2 diabetes.