Pharmacophore based 3DQSAR of phenothiazines as specific human butyrylcholinesterase inhibitors for treatment of Alzheimer's disease

Quantitative three dimensional structure activity relationship (3D-QSAR) studies were performed on phenothiazine derivatives as Butyrylcholinesterase (BuChE) inhibitors. Pharmacophore Alignment and Scoring Engine (PHASE) was used to develop predictive Common Pharmacophore Hypotheses (CPHs). The alig...

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Bibliographic Details
Published in:	Current computer-aided drug design Vol. 10; no. 4; p. 335
Main Authors:	Kundaikar, Harish S, Agre, Neha P, Degani, Mariam S
Format:	Journal Article
Language:	English
Published:	United Arab Emirates 01-01-2014
Subjects:	Alzheimer Disease - drug therapy Butyrylcholinesterase - chemistry Butyrylcholinesterase - metabolism Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - pharmacology Cholinesterase Inhibitors - therapeutic use Drug Discovery Humans Models, Molecular Phenothiazines - chemistry Phenothiazines - pharmacology Phenothiazines - therapeutic use Quantitative Structure-Activity Relationship
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Summary:	Quantitative three dimensional structure activity relationship (3D-QSAR) studies were performed on phenothiazine derivatives as Butyrylcholinesterase (BuChE) inhibitors. Pharmacophore Alignment and Scoring Engine (PHASE) was used to develop predictive Common Pharmacophore Hypotheses (CPHs). The alignment thus obtained was used for Comparative Molecular Field Analysis (CoMFA)/Comparative Molecular Similarity Indices Analysis (CoMSIA) model development. A fourpoint common pharmacophore hypothesis, comprising of one acceptor, one hydrophobic region and two aromatic ring centres was generated. A structurally diverse set of 80 molecules was used of which 56 were grouped into training set to develop the model and the rest 24 molecules into test set to validate the CoMFA/CoMSIA models. The models so developed showed a good r(2)predictive of 0.7587 for CoMFA and 0.7737 for CoMSIA. CoMFA and CoMSIA models had excellent Q(2) (cross-validated coefficient) of 0.7125 and 0.7093, respectively which showed high correlative and predictive abilities of the models. The 3-D contour maps of CoMFA/CoMSIA provided interpretable explanation of SAR for the compounds and also permitted interesting conclusions about the substituent effects on the phenothiazine derivatives. The outcomes of the study would help in the rational design of novel and potent therapeutic agents as specific BuChE inhibitors for symptomatic or disease modifying treatment of AD.
ISSN:	1875-6697
DOI:	10.2174/1573409911666150318203528