In silico and in vitro studies of thiosemicarbazone-indole hybrid compounds as potent α-glycosidase inhibitors. (April 2022)

• Record Type: Journal Article
• Authors: Bakherad, Zohreh; Bakherad, Hamid; Sepehri, Saghi; Faramarzi, Mohammad Ali; Mahnam, Karim; Mojtabavi, Somayeh; Mahdavi, Mohammad
• Is Part Of: Computational biology and chemistry. Volume 97(2022)
• Publication Date: 2022-04
• Subjects: DM Diabetes mellitus -- T2DM Type-II diabetes mellitus -- IDF International Diabetes Federation -- GI Gastrointestinal -- AGIs α-glucosidase inhibitors -- pNPG p-nitrophenyl glucopyranoside -- DMSO Dimethyl Solfoxde -- Km Michaelis-Menten constant -- Ki Experimental inhibitor constant -- ADT AutoDock Tools -- GROMACS GROningen MAchine for Chemical Simulations -- LGA Lamarckian Genetic Algorithm -- MD molecular dynamics -- MM/PBSA molecular mechanics Poisson/Boltzmann surface area -- PME particle mesh ewald -- PDB protein data bank -- RMSD root mean square deviation -- RMSF root mean square fluctuation -- SPC simple point charge -- OSDD open source drug discovery consortium -- SAR Structure-activity relationship; Thiosemicarbazone-indole hybrids -- α-Glycosidase -- Molecular dynamic -- MM/PBSA -- Drug-likeness; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2022.107642
• Languages: English
• ISSNs: 1476-9271

Abstract

Abstract: It is essential to study α-glucosidase enzyme (EC 3.2.1.20) inhibitors because of their physiological role as well as their clinical relevance. In previous research, a novel series of thiosemicarbazone-indole hybrid compounds were synthesized and reported. In the current research, α-glucosidase inhibitory activity of the derivatives was evaluated and then in silico studies were carried out on screened compounds. All derivatives exhibited a magnificent α-glucosidase inhibitory activity (IC50 = 27.0 ± 1.0–97.4 ± 1.5 µM) toward the acarbose as reference drug (IC50 = 750.0 ± 1.5 µM). Compound 1i having phenyl ring at the thiosemicarbazone moiety and the trimethoxymethyl substituent at phenyl moiety of C2 position of indole ring was the most potent compound (IC50 = 27.0 ± 1.0 µM) among other compounds. A kinetic study of 1i revealed that is a competitive inhibitor against α-glucosidase. Moreover, the molecular docking studies established that screened derivatives interacted with the essential amino acids in the active site. Finally, based on the molecular dynamics simulations and free binding energy calculations, complexes 1d, 1i and 1k with α-glucosidase showed a good stability in the active site. Van der Waals and electrostatic interactions also exhibited the most contributions to the stability of these complexes. Moreover, all the screened compounds showed agreeable ADME properties for oral bio-availability, and good drug-likeness. Graphical Abstract: ga1 Highlights: Thiosemicarbazone-indole hybrid compounds exhibit an excellent α-glucosidase inhibitory activity. Kinetic study of 1i revealed that it is a competitive inhibitor against α-glucosidase. MD simulations have emphasized the opportunities to improve the binding.