Exploring the Chemical Reactivity, Molecular Docking, Molecular Dynamic Simulation and ADMET Properties of a Tetrahydrothienopyridine Derivative Using Computational Methods

• Published in: Crystals (Basel) 2023-07, Vol.13 (7), p.1020
• Main Authors: Bakheit, Ahmed H., Attwa, Mohamed W., Kadi, Adnan A., Ghabbour, Hazem A., Alkahtani, Hamad M.
• Format: Article
• Language: English
• Subjects: Adenosine; Analysis; Candidates; Chemical bonds; Chemical properties; chemical reactivity; Crystal structure; Free energy; Hirshfeld surface analysis; Hydrogen bonds; Ligands; Methods; Molecular docking; Molecular dynamics; molecular electrostatic potential; Molecular interactions; non-covalent interaction–reduced-density gradient analysis; Pharmacology; Proteins; Pyridine; Quantum theory; quantum theory of atoms in molecules; Simulation; Software; Surface analysis (chemical)
• ISSN: 2073-4352; 2073-4352
• DOI: 10.3390/cryst13071020

This study investigates the crystal structure, physicochemical properties, and pharmacokinetic profile of Ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (EAMT) as a potential therapeutic agent. The crystal structure was analyzed using Hirshfeld surface analysis in conjunction with the quantum theory of atoms in molecules (QT-AIM). Non-covalent interactions were evaluated through reduced-density gradient reduction, revealing that the EAMT crystal is stabilized by hydrogen bonds between EAMT molecules in the crystal and between EAMT molecules and water molecules. The molecular electrostatic nature of interactions was examined using MESP, while global and local descriptors were calculated to assess the compound’s reactivity. Molecular docking with the Adenosine A1 receptor was performed and validated through a 50 ns molecular dynamics simulation (MDS). Results suggest that EAMT influences protein structure, potentially stabilizing specific secondary structure elements. The compactness analysis showed a slightly more compact protein conformation and a marginally increased solvent exposure in the presence of the EAMT ligand, as indicated by Rg and SASA values. The total binding free energy (ΔG total) was determined to be −114.56 kcal/mol. ADMET predictions demonstrated EAMT’s compliance with Lipinski’s and Pfizer’s rule of five, indicating good oral availability. The compound may exhibit low-potency endocrine activity. In conclusion, EAMT presents potential as a therapeutic candidate, warranting further exploration of its molecular interactions, pharmacokinetics, and potential safety concerns.