title: Novel butyrylcholinesterase inhibitors through pharmacophore modeling, virtual screening and DFT-based approaches along-with design of bioisosterism-based analogues.
abstract: Ligand and structure-based pharmacophore models were used to identify the important chemical features of butyrylcholinesterase (BChE) inhibitors. A training set of 16 known structurally diverse compounds with a wide range of inhibitory activity against BChE was used to develop a quantitative ligand-based pharmacophore (Hypo1) model to identify novel BChE inhibitors in virtual screening databases. A structure-based pharmacophore hypothesis (Phar1) was also developed with the ligand-binding site of BChE in consideration. Further, the models were validated using test set, Fisher's Randomization and Leave-one-out validation methods. Well-validated pharmacophore hypotheses were further used as 3D queries in virtual screening and 430 compounds were finally selected for molecular docking analysis. Subsequently, ADMET, DFT and chemical similarity search were employed to narrow down on seven compounds as potential drug candidates. Analogues of the best hit were further developed through a bioisosterism-guided approach to further generate a library of potential BChE inhibitors.
authors.affiliation: DBT-Bioinformatics Infrastructure Facility, Centre for Biotechnology and Bioinformatics, School of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India.
authors.forename: Dhrubajyoti
authors.initials: D
authors.lastname: Gogoi
authors.affiliation: Centre for Biotechnology and Bioinformatics, School of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India.
authors.forename: Amrita Kashyap
authors.initials: AK
authors.lastname: Chaliha
authors.affiliation: Department of Chemistry, School of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India.
authors.forename: Diganta
authors.initials: D
authors.lastname: Sarma
authors.affiliation: DBT-Bioinformatics Infrastructure Facility, Centre for Biotechnology and Bioinformatics, School of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India.
authors.forename: Bibhuti Bhusan
authors.initials: BB
authors.lastname: Kakoti
authors.affiliation: Centre for Biotechnology and Bioinformatics, School of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India. Electronic address: alakkrburagohain@gmail.com.
authors.forename: Alak Kumar
authors.initials: AK
authors.lastname: Buragohain
mesh_terms: D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D002091:Butyrylcholinesterase
keywords: ADMET; Butyrylcholinesterase (BChE); DFT; Molecular docking; Pharmacophore modeling