Kinetics and structure-activity relationship studies on pregnane-type steroidal alkaloids that inhibit cholinesterases.
The mechanism of inhibition of acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) enzymes by 23 pregnane-type alkaloids isolated from the Sarcococca saligna was investigated. Lineweaver-Burk and Dixon plots and their secondary replots showed that the majority of these compounds, that is 1, 4, 5, 6, 9, 10, 12, 13, 15-19, and 21 were found to be noncompetitive inhibitors of both enzymes. Compounds 8, 20, 22, and 23 were determined to be uncompetitive inhibitors of BChE, while compounds 11 and 14 were found to be uncompetitive and linear mixed inhibitors of AChE, respectively. Ki values were found to be in the range of 2.65-250.0 microM against AChE and 1.63-30.0 microM against BChE. The structure-activity relationship (SAR) studies suggested that the major interaction of the enzyme-inhibitor complexes are due to hydrophobic and cation-pi interactions inside the aromatic gorge of these cholinesterases. The effects of various substituents on the activity of these compounds are also discussed in details.
Khalid
Asaad
A
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Karachi 75270, Pakistan.
Zaheer-ul-Haq
Anjum
Shazia
S
Khan
M Riaz
MR
Atta-ur-Rahman
Choudhary
M Iqbal
MI
D000110:Acetylcholinesterase / Q000187:drug effects; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D011278:Pregnanes / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D011278:Pregnanes; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase