title: Identification of molecular descriptors for design of novel Isoalloxazine derivatives as potential Acetylcholinesterase inhibitors against Alzheimer's disease.
abstract: In Alzheimer's disease (AD), the level of Acetylcholine (ACh) neurotransmitter is reduced. Since Acetylcholinesterase (AChE) cleaves ACh, inhibitors of AChE are very much sought after for AD treatment. The side effects of current inhibitors necessitate development of newer AChE inhibitors. Isoalloxazine derivatives have proved to be promising (AChE) inhibitors. However, their structure-activity relationship studies have not been reported till date. In the present work, various quantitative structure-activity relationship (QSAR) building methods such as multiple linear regression (MLR), partial least squares ,and principal component regression were employed to derive 3D-QSAR models using steric and electrostatic field descriptors. Statistically significant model was obtained using MLR coupled with stepwise selection method having r2= .9405, cross validated r2(q2) = .6683, and a high predictability (pred_r2= .6206 and standard error, pred_r2se = .2491). Steric and electrostatic contribution plot revealed three electrostatic fields E_496, E_386 and E_577 and one steric field S_60 contributing towards biological activity. A ligand-based 3D-pharmacophore model was generated consisting of eight pharmacophore features. Isoalloxazine derivatives were docked against human AChE, which revealed critical residues implicated in hydrogen bonds as well as hydrophobic interactions. The binding modes of docked complexes (AChE_IA1 and AChE_IA14) were validated by molecular dynamics simulation which showed their stable trajectories in terms of root mean square deviation and molecular mechanics/Poisson-Boltzmann surface area binding free energy analysis revealed key residues contributing significantly to overall binding energy. The present study may be useful in the design of more potent Isoalloxazine derivatives as AChE inhibitors.
authors.affiliation: a Computational Biology Laboratory, Department of Biotechnology and Bioinformatics , North-Eastern Hill University , Shillong 793022 , India.
authors.forename: Arun Bahadur
authors.initials: AB
authors.lastname: Gurung
authors.affiliation: b Molecular Biology Laboratory, Department of Biotechnology and Bioinformatics , North-Eastern Hill University , Shillong 793022 , India.
authors.forename: Kripamoy
authors.initials: K
authors.lastname: Aguan
authors.affiliation: c Center for Advanced Studies in Chemistry , North-Eastern Hill University , Shillong 793022 , India.
authors.forename: Sivaprasad
authors.initials: S
authors.lastname: Mitra
authors.affiliation: a Computational Biology Laboratory, Department of Biotechnology and Bioinformatics , North-Eastern Hill University , Shillong 793022 , India.
authors.forename: Atanu
authors.initials: A
authors.lastname: Bhattacharjee
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D020816:Amino Acid Motifs; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D005415:Flavins / Q000737:chemistry* / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D016018:Least-Squares Analysis; D016014:Linear Models; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D002800:Cholinesterase Inhibitors; D005415:Flavins; D058851:GPI-Linked Proteins; C008173:isoalloxazine; C548244:ACHE protein, human; D000110:Acetylcholinesterase
keywords: 3D-QSAR; Acetylcholinesterase (AChE); Isoalloxazine; molecular docking, molecular dynamics simulation and MM/PBSA; pharmacophore