Computer-Aided Design of Novel Acrylamido Derivatives as Potential Oral Antidiabetic Agents.

INTRODUCTION/OBJECTIVE: Due to the significant problem of the pharmacokinetic properties of available oral antidiabetic drugs, it is necessary to focus on developing novel oral agents. This study utilized in silico methods to design novel GLP-1 receptor agonists as potential oral antidiabetic drugs based on the most promising studies in the literature. In the framework of available studies, novel methyl (S, E)-3-(4-substitutedphenyl)-2-(3-(3,4-dichlorophenyl) acrylamido)propanoate and (E)-3-(4-(2-(3-(3,4-dichlorophenyl)acrylamido) ethyl) phenyl) propanoic acid derivatives were designed as GLP-1 agonists.

METHODS: Molecular docking, molecular dynamics simulations, and ADME analysis were applied to clarify the structure-activity relationship of compounds. Compounds were evaluated against specific protein targets, including the glucagon-like peptide-1 receptor, the extracellular domain of the GLP-1 receptor, the extracellular domain of the human calcium-sensing receptor, the human maltase-glucoamylase enzyme, and the human dipeptidyl peptidase IV enzyme.

RESULTS: Despite the various results obtained on the specific molecule and target, protein-ligand interactions of compounds were found to be strongly comparable to native ligands. Compound 3 and compound 8 showed very similar binding energies compared to the native ligands against the 6X19 and 3C5T protein targets, respectively, and exhibited similar stability in a biological environment.

DISCUSSION: The computational results indicated that the molecules have significant binding properties. Therefore, it would be appropriate to test compounds 3 and 8 for antidiabetic efficacy due to their strong and stable binding properties.

CONCLUSION: The computatıonal results revealed that compounds 3 and 8 are potential compounds for their anti-diabetic activities.