HIGH-THROUGHPUT STRUCTURE BASED VIRTUAL SCREENING TARGETING CNS FOR INHIBITED ACETYLCHOLINESTERASE REACTIVATIONAbstract
Organophosphorus (OP) nerve agents blocks acetylcholinesterase and do not allow the degradation of acetylcholine. Post-treatment of organophosphate poisoning involves the treatment with oxime reactivators as an antidote, which will dephosphorylate the phosphate bond between enzyme and nerve agent. Due to CNS permeability failure of these oximes, the introduction of low molecular non-oximes has become a challenging role for reactivation of inhibited acetylcholinesterase. In-silico high-throughput structure-based virtual screening and docking by using LOPAC database targeting CNS for inhibited acetylcholinesterase reactivation. For the identification of an active site of AChE enzyme and high throughput virtual screening, Inventus™ software was being used. ADME analysis for the selection of leads which can follow up Lipinski rule of 5 and CNS parameters for permeation. Further docking studies of selected lead candidates was done using Schrodinger software. By taking various CNS parameters into consideration hits were selected. For further refinement docking was performed, and the best lead obtained with glide XP docking score -11.656 Kcal/mol. The best lead candidates passed CNS permeation parameters range and have shown well binding with Acetylcholinesterase enzyme as that of standards.
N. Darmwal and B. K. Singh *
Department of Pharmaceutical Sciences, Kumaun University Campus, Bhimtal, Nainital, Uttarakhand, India.
30 March 2019
09 August 2019
12 August 2019
01 January 2020