Current Computer-Aided Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811
USA

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Pharmacophore Based 3DQSAR of Phenothiazines as Specific Human Butyrylcholinesterase Inhibitors for Treatment of Alzheimer’s Disease

Author(s): Harish S. Kundaikar, Neha P. Agre, Mariam S. Degani.

Abstract:

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 r2predictive of 0.7587 for CoMFA and 0.7737 for CoMSIA. CoMFA and CoMSIA models had excellent Q2 (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.

Keywords: 3D-QSAR, Alzheimer’s disease, butyrylcholinesterase inhibitors, CoMFA and CoMSIA, multi-targeting inhibitors, pharmacophore, PHASE.

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Article Details

VOLUME: 10
ISSUE: 4
Year: 2014
Page: [335 - 348]
Pages: 14
DOI: 10.2174/1573409911666150318203528
Price: $58