Identification of Novel β3-Adrenoceptor Agonists Using Energetic Analysis, Structure Based Pharmacophores and Virtual Screening

Author(s): Parul Tewatia, B.K. Malik, Shakti Sahi

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 15 , Issue 8 , 2012

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β3 Adrenergic receptor (β3-AR), is a potential therapeutic target for the treatment of type II diabetes and obesity. We report the identification of novel compounds as β3-AR agonists by integrating different approaches of energetic analysis, structure based pharmacophore designing and virtual screening. In a step wise filtering protocol, structure based virtual screening of 2,33,450 compounds was done. These molecules were docked into the active site of the receptor utilizing three levels of accuracy; ligands passing the HTVS (high throughput virtual screening) step were subsequently analyzed in Glide SP (Standard Precision) and finally in Glide XP (Extra Precision) to estimate the receptor ligand binding affinities. In the second step a total of 300 pharmacophore hypotheses were generated from a set of known and diverse β3-AR agonists. The best hypothesis showed six features: three hydrogen bond acceptors, one positively charged group, and two aromatic rings. To cross validate, pharmacophore filtering was done on the set of shortlisted compounds from structure based VS (virtual screening). The different screening techniques employed were validated using enrichment factor calculations. The energetic based Pharmacophore performed fairly well at distinguishing active from the inactive compounds and yielded a greater diversity of active molecules whereas the number of actives retrieved in the case of structure based screening was the highest.

Keywords: Beta 3 adrenergic receptor, enrichment factor, pharmacophore, virtual screening, type II diabetes, β3-AR, e-pharmacophore modeling, Glide SP, Glide XP, Virtual Screening

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Article Details

Year: 2012
Published on: 27 August, 2012
Page: [623 - 640]
Pages: 18
DOI: 10.2174/138620712802650559
Price: $65

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