title: Dual binding site and selective acetylcholinesterase inhibitors derived from integrated pharmacophore models and sequential virtual screening.
abstract: In this study, we have employed in silico methodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer's randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties.
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S.Nagar, Punjab 160 062, India.
authors: Shikhar
authors: S
authors: Gupta
authors: Amrita Centre for Nanosciences and Molecular Medicine (ACNSMM), Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham University, Ponekkara, Kochi, Kerala State 682 041, India.
authors: C Gopi
authors: CG
authors: Mohan
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015203:Reproducibility of Results; D014584:User-Computer Interface
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase