title: Structural insight into the inhibition of acetylcholinesterase by 2,3,4, 5-tetrahydro-1, 5-benzothiazepines.
abstract: Benzothiazepines 1-3 inhibited acetylcholinesterase (AChE; EC 3.1.1.7) enzyme in a concentration-dependent fashion with IC(50) values of 1.0 +/- 0.002, 1.2 +/- 0.005 and 1.3 +/- 0.001 microM, respectively. By using linear-regression equations, Lineweaver-Burk, Dixon plots and their secondary replots were constructed which indicated that compounds 1-3 are non-competitive inhibitors of AChE with K(i) values of 0.8 +/- 0.04, 1.1 +/- 0.002, and 1.5 +/- 0.001 microM, respectively. Molecular docking studies revealed that all the compounds are completely buried inside the aromatic gorge of AChE, extending deep into the gorge of AChE. A comparison of the docking results of compounds 1-3 displayed that these compounds generally adopt the same binding mode in the active site of AChE. The superposition of the docked structures demonstrated that the non-flexible benzothiazepine always penetrate into the aromatic gorge through the six-membered ring A, which allowed the ligands to interact simultaneously with more than one subsites of the active center of AChE. The higher AChE inhibitory potential of compounds 1-3 was found to be the cumulative effect of hydrophobic contacts and pi-pi interactions between the ligands and AChE. The relatively high affinity of benzothiazepine 1 with AChE was found to be due to additional hydrogen bond in benzothiazepine 1-AChE complex. The results indicated that substitution of halogen and methyl groups by hydrogen at aromatic ring of the benzothiazepine decreased the affinity of these molecules towards enzyme that may be due to the polar non-polar repulsions of these moieties with the amino acid residues in the active site of AChE. The observed binding modes of benzothiazepines 1-3 in the active site of AChE explain the affinities of benzothiazepines and provide a rational basis for the structure-based drug design of benzothiazepines with improved pharmacological properties.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan. sarfraz_509@yahoo.com
authors.forename: Sarfraz A
authors.initials: SA
authors.lastname: Nawaz
authors.forename: Sumaira
authors.initials: S
authors.lastname: Umbreen
authors.forename: Asaad
authors.initials: A
authors.lastname: Kahlid
authors.forename: Farzana L
authors.initials: FL
authors.lastname: Ansari
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006859:Hydrogen / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C106746:1,5-benzothiazepine; D002800:Cholinesterase Inhibitors; D013841:Thiazepines; D006859:Hydrogen; D000110:Acetylcholinesterase