INTRODUCTION: Alzheimer's disease (AD) is a form of dementia which affects majority of the people. It is characterized by memory loss and other cognitive functions disabilities and is one of the most challenging neurodegenerative disorders to treat, because of its progressive nature. The disease affects millions of people all around the world, and the number of those affected is expanding every day. In the previous study, the 4-phthalimidobenzenesulfonamide derivatives were synthesized as AChE and BChE inhibitors and here we are aiming to further reporting in-silico studies of these compounds for efficient drug discovery process and to find out the potential lead compounds. METHODS: In-silico characterization included: Density functional theory (DFT) studies, 3D-QSAR, ADMET properties, molecular docking and molecular dynamic simulations. The geometries of all derivatives were optimized using B3LYP method and 6-311G basis set. RESULTS: The findings of the current study revealed that 4-phthalimidobenzenesulfonamide derivatives exhibited a reactive electronic property which is essential for anti-cholinesterase activity. Moreover, optimized structures were subjected to molecular docking studies with targeted protein. The compound 2c and 2g showed excellent binding score of -37.44 and -33.67 kJ/mol with BChE and AChE, respectively and exhibited strong binding affinity. The potent derivatives produced stable complex with amino acid residues of active pocket of both BChE and AChE. The stability of protein-ligand complexes was determined by molecular dynamic simulation studies and results were found in correlation with molecular docking findings. CONCLUSION: Findings of current study suggested that these derivatives are potent inhibitors of cholinesterase enzyme.
Title: Synthesis and molecular docking studies of some 4-phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors Soyer Z, Uysal S, Parlar S, Tarikogullari Dogan AH, Alptuzun V Ref: J Enzyme Inhib Med Chem, 32:13, 2017 : PubMed
A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC(50)= 1.35 +/- 0.08 microM), while compound 3 exhibited the highest inhibition against BuChE (IC(50)= 13.41 +/- 0.62 microM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.
